DESC:FIELD OF THE INVENTION

The present invention relates to a process for preparation of 2-((1-benzylpiperidin-4-yl) methyl)-5,6-dimethoxy- 2,3-dihydro- 1H-inden-1-one Hydrochloride (Donepezil hydrochloride) of formula I . The present invention also relates to a intermediates of Donepezil, (E)-2-((1-benzylpiperidin-4-yl) methylene)- 5,6-dimethoxy- 2,3-dihydro- 1H-inden-1-one hydrochloride compound of formula V which is further converted to highly pure intermediates of Donepezil, (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV.

BACKGROUND OF THE INVENTION

Donepezil hydrochloride is a useful memory enhancer introduced by the Japanese pharmaceutical company Eisai. Its preparation was described in patent no. EP 296560. In this patent Donepezil was produced by reaction of 5,6-dimethoxy-1-indanone with 1-benzyl-4-formylpiperidine in the presence of a strong base, such as lithium diisopropylamide followed by reduction of the double bond.

Organic Process Research & Development 2008, 12, 731–735 describes process for the synthesis of Donepezil. According to this article, condensation of 1-benzylpiperidine-4-carboxaldehyde (2) 5,6-dimethoxy indanone (3) in the presence of a strong base such as n-butyl lithium and diisopropylamine in hexamethyl phosphoric amide (HMPA) under inert atmosphere at -78 °C, and finally catalytic reduction of the double bond compound 4 with 10% Pd/C in tetrahydrofuran (THF) furnished donepezil free base (Figure 1, Path A). This process suffered from several disadvantages: (a) use of hazardous and pyrophoric reagents such as n-butyl-lithium, (b) unacceptable process solvents such as hexane and HMPA, (c) the requirement for special equipment to attain the lower temperatures required for the condensation of 2 and 3 and (d) purification of 4 and free base of 1 by column chromatography.

Patent application EP 711756 describes the preparation of Donepezil by reaction of 5,6-dimethoxy-1-indanone with pyridin-4-aldehyde to give 5,6-dimethoxy-2-(pyridin-4-yl)methylene indan-1-one further the reaction with benzyl bromide afforded 1-benzyl-4-(5,6-dimethoxyindan-1-on-2-ylidene)methylpyridinium bromide. Hydrogenation in the presence of platinum oxide to obtain Donepezil.

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-2,3-dihydro-1H-inden-1-one compound of formula-II,

Formula-II
with 1-benzylpiperidine-4-carbaldehyde compound of formula-III,

Formula-III
for the preparation of (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV

Formula IV
formation of an impurity at 0.47-0.49 RRT occurs about 15% to 10%. The amount of impurity formation varies depending upon reaction conditions, amount of solvent, nature of solvent used. It is advantageous to remove impurity at this stage; otherwise it hinders the process of hydrogenation of (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV and further it gets converts to hydrochloride in the presence of hydrochloric acid, hence difficult to remove. Further hydrogenation is required to reduce the double bond of (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV, the inventors have further found that during hydrogenation of compound of formula VI in the presence of palladium catalyst impurity is generated at RRT 0.29-0.32. Once the impurity is generated at RRT 0.29-0.32 in the reaction mixture it is difficult to remove. An additional step for purification of impurity is required to obtain purified 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 2-((1-benzylpiperidin-4-yl)methyl)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one Hydrochloride (Donepezil HCl) of formula I

Formula I
comprises:
a) condensation reaction of 5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula-II with 1-benzylpiperidine-4-carbaldehyde compound of formula-III to obtain of (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV;

b) treating (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV with acid and converting to pharmaceutically acceptable salts and isolating (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one Hydrochloride compound of formula V;
c) treating the compound of formula V with base to (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV;
d) hydrogenating (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV in presence of palladium catalyst and an organic solvent;
e) treating the donepezil base with acid and converting to pharmaceutically acceptable salts.

In another aspect, present invention provides a process for the preparation of (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV comprises:

a) condensation reaction of 5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula-II

with 1-benzylpiperidine-4-carbaldehyde compound of formula-III;

in the presence of phase transfer catalyst and base with methylene dichloride.
b) treating (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV with acid and converting to pharmaceutically acceptable salts and isolating (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one Hydrochloride compound of formula V;
c) treating the compound of formula V with base to (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV;
d) washing with ketone solvent.

In another aspect, present invention provides a process for the purification of E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV to remove impurity comprising
a) treating the reaction mixture with acid wherein pH is below 1.0;
b) treating the reaction mixture with base wherein pH is greater than 11.0;
c) repeat step (a) and step (b) up to impurity at 0.49 RRT NMT 0.3 %;
d) washing with ketone solvent at 55-65°C;

In another aspect, present invention provides a process for the preparation of 2-((1-benzylpiperidin-4-yl)methyl)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one Hydrochloride (Donepezil hydrochloride) of formula I comprises:

a) hydrogenating (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV in presence of Palladium catalyst and an organic solvent;
b) treating the donepezil base with acid and converting to pharmaceutically acceptable salts.

c) dissolve in alcoholic solvent;
d) precipitated 2-((1-benzylpiperidin-4-yl)methyl)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one Hydrochloride (Donepezil hydrochloride) of formula I with diisopropyl ether.

Accordingly, in another aspect, present invention provides an isolated compound (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one Hydrochloride compound of formula V

DETAILED DESCRIPTION OF DRAWINGS:
FIGURE 1: is a HPLC chromatograph of result of analysis of Crude (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one, Compound of Formula IV.
FIGURE 2: is a HPLC chromatograph of result of analysis of Purification in Ethyl acetate of (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one, Compound of Formula IV.
FIGURE 3: is a HPLC chromatograph of result of analysis of Purification in Diisopropyl ether of (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one, Compound of Formula IV.
FIGURE 4: is a HPLC chromatograph of result of analysis of Purification in Isopropyl acetate (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one, Compound of Formula IV.
FIGURE 5: is a HPLC chromatograph of result of analysis of Crude of Example 2 (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one, Compound of Formula IV.
FIGURE 6: is a HPLC chromatograph of result of analysis of Ist Acid treatment of Example 2 (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one, Compound of Formula IV.
FIGURE 7: is a HPLC chromatograph of result of analysis of Ist Base treatment of Example 2 (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one, Compound of Formula IV.
FIGURE 8: is a HPLC chromatograph of result of analysis of IInd Acid treatment of Example 2 (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one, Compound of Formula IV.
FIGURE 9: is a HPLC chromatograph of result of analysis of IInd Base treatment of Example 2 (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one, Compound of Formula IV.
FIGURE 10: is a HPLC chromatograph of result of analysis of treatment with Acetone of Example 2 (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one, Compound of Formula IV.
FIGURE 11: is a HPLC chromatograph of result of analysis of Crude of Example 3 (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one, Compound of Formula IV.
FIGURE 12: is a HPLC chromatograph of result of analysis of Ist Acid treatment of Example 3 (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one, Compound of Formula IV.
FIGURE 13: is a HPLC chromatograph of result of analysis of Ist Base treatment of Example 4 (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one, Compound of Formula IV.
FIGURE 14: is a HPLC chromatograph of result of analysis of IInd Acid treatment of Example 3 (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one, Compound of Formula IV.
FIGURE 15: is a HPLC chromatograph of result of analysis of IInd Base treatment of Example 3 (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one, Compound of Formula IV.
FIGURE 16: is a HPLC chromatograph of result of analysis of treatment with Acetone of Example 3 (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one, Compound of Formula IV.
FIGURE 17: is a HPLC chromatograph of result of analysis of crude 2-((1-benzylpiperidin-4-yl)methyl)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one Compound of Formula I
FIGURE 18: is a HPLC chromatograph of result of analysis of purified 2-((1-benzylpiperidin-4-yl) methyl)-5,6-dimethoxy- 2,3-dihydro-1H-inden-1-one Hydrochloride (Donepezil Hydrochloride) of formula I

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the terms below have the meanings indicated.

The singular forms "a," "an," and "the" may refer to plural articles unless specifically stated otherwise.

The term "about," as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term "about" should be understood to mean that range which would encompass the recited value and the range which would be included by rounding up or down to that figure as well, taking into account significant figures.

In the first embodiment the present invention provides an improved process for the preparation of highly pure 2-((1-benzylpiperidin-4-yl)methyl)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one Hydrochloride (Donepezil HCl) of formula I

comprises:
a) condensation reaction of 5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula-II with 1-benzylpiperidine-4-carbaldehyde compound of formula-III to obtain of (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV;

b) treating (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV with acid and converting to pharmaceutically acceptable salts and isolating (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one Hydrochloride compound of formula V;

c) treating the compound of formula V with base to (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV;

d) hydrogenating (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV in presence of Palladium catalyst and an organic solvent;
e) treating the Donepezil base with acid and converting to pharmaceutically acceptable salts.

According to another embodiment, there is provided a process for the preparation of (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV in high purity and better yields by the condensation of 5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula II

with 1-benzylpiperidine-4-carbaldehyde compound of formula III;

to obtain of (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV, in the presence of phase transfer catalyst and base with methylene dichloride as solvent. Specifically the reaction is conducted at 25°C-70°C in methylene dichloride for about 2-10 hours for completion of reaction.

The (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV was further treated with acid and isolated (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one Hydrochloride compound of formula V which was purified to remove impurity.

According to above embodiment, phase-transfer catalyst is a quaternary ammonium salt such as tetra-n-butylammonium chloride, tetra-n-butylammonium bromide (TBAB), and methyltri-n-octylammonium chloride. Most preferabl phase-transfer catalyst is Tetrabutylammonium halides, such as tetrabutylammonium bromide (TBAB).

According to above embodiment, organic solvent comprises ethers, alcohols, chlorinated hydrocarbons, esters, ketones, hydrocarbons, polar aprotic solvents, water and mixtures thereof.

According to another embodiment, there is provided a process for the preparation (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one Hydrochloride compound of formula V comprises treating (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV with acid and converting to pharmaceutically acceptable salts and isolating (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one Hydrochloride compound of formula V.

According to another embodiment, the isolated (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one Hydrochloride compound of formula V was treated with base to obtain (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV.

According to above embodiment, acid is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or boric acid and base is selected from sodium hydroxide and potassium hydroxide.

According to above embodiment, is further purified with (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV ketone solvent, wherein ketone solvent are 2-pentanone, 3-pentanone, 2-hexanone, methyl isobutyl ketone, 2-heptanone, 3-heptanone, 4-heptanone, diisobutyl ketone, mesityl oxide, phorone, 2-octanone, cyclohexanone, methylcyclohexanone, isophorone, 2,4-pentanedione or 2,5-hexanedione, acetone or methyl ethyl ketone.

The purified (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV is isolated in high purity greater than 99.5% preferably greater than 99.8%.

According to another embodiment, there is provided a process for the preparation of highly pure 2-((1-benzylpiperidin-4-yl)methyl)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one Hydrochloride (Donepezil HCl) of formula I which includes hydrogenating (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV, in the presence of palladium catalyst to produce and isolating the substantially pure donepezil or a salt thereof. Specifically hydrogenation of (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV is carried out using palladium 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 ethers, alcohols, chlorinated hydrocarbons, esters, ketones, hydrocarbons, polar aprotic solvents, water and mixtures thereof and preferably ethyl acetate is used.

According to embodiment, hydrogenation reactions is carried out using palladium catalyst and it was found that using palladium catalyst with solvent, impurity at RRT 0.32 is substantial controlled depending upon the solvent system used during the reaction. Palladium catalyst can be selected from Palladium oxide, Palladium on carbon and preferably Palladium 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 unreacted Formula IV not more than 0.8%. The reaction mixture is filtered to recover the catalyst. The filtrate is concentrated and crude donepezil is dissolved in aq. Solution of Acid preferably HCl and washed with organic solvent preferably Ethyl acetate. The aqueous layer is treated with methylene chloride (MDC).

The resulting mixture is concentrated and the product obtained is recrystallized from methanol and diisopropyl ether to obtain highly pure donepezil hydrochloride having purity greater than 99.2% preferably greater than 99.9%.

Major advantages realized in the present invention are high purity and high yields. The formation of impurity at RRT 0.29-0.32 has been restricted by making use of Palladium catalyst with solvent system of methylene chloride and methanol. This avoids the use of tedious and cumbersome technique i.e. chromatographic purification as additional step of purification.

The stage I impurity is removed from (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one Hydrochloride compound of formula V by and further treatment with acid and base of (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV.

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
EXAMPLE 1 : Preparation of (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV

5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (100g) was dissolved in methylene dichloride (350ml) followed by addition of TBAB (10.0g) cooled to 15 ± 5 temperature, add sodium hydroxide solution 250 ml. 1-benzylpiperidine-4-carbaldehyde (126.8g) solution in dichloromethane was added to reaction mass below 20 °C. The temperature of the reaction mass was gradually raised to 40 to 45°C and was stirred for 6 hours. The reaction mass was concentrated under vacuum. The slurry was filtered and the product was washed with water to give (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one. Result: Dry wt. 195 g, HPLC purity: 96.937%, Impurity at RRT 0.47 – 0.49: 1.275 % and Impurity at RRT 1.73 0.398 %.

EXAMPLE 2: Preparation and Purification of (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV

To reaction mass from example 1 (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one was charged in water and treated with Diluted HCl solution (140 To 150 ml ) pH adjusted to below 1.0. (Preparation of Diluted HCl : 70 ml HCl 35% + 70 ml Process Water.). The reaction mixture was stirred for 2 to 4hr at 20-45°C and after completion of reaction, the reaction mass filtered and washed with DM water. The reaction mass was treated with around 10 % NaOH Solution (200 ml To 220 ml ) and pH was adjusted to not less than 11.5, [Preparation of 10 % NaOH Solution : 20 gm NaOH dissolved in 200 ml of Process Water] The reaction mixture was stirred for 2 to 4hr at 20-45°C and after completion of reaction, the reaction mass was filtered and washed with water. The process of acid and base treatment was repeated up to unknown impurity at 0.47-0.49 RRT was NMT 0.3 %. After the completion of acid base treatment reaction mass was treated with acetone. The temperature of the reaction mass was gradually raised to 55 to 65°C and was stirred for 0.5 hours. Cooled to 20 to 30 °C which was filtered with acetone to obtain 142 to 180 gm of (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one having a purity of 99.8% by HPLC and % Yield : 91.84%.

EXAMPLE 3: Preparation and Purification of (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV
Charge (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one in water and add adjust pH to less than 1.0 by using dilute HCl solution (50%) (140 to 150 ml). Stir the reaction mass for 2 hr at 20 – 45°C. Filter the reaction mass and washed with water. Charge the obtained solid in 10% Sodium hydroxide solution (200 ml to 220 ml) and pH adjusted to not less than 11.5. Stir the reaction mass for 2 – 4 hr at 20 – 45°C. Filter the reaction mass and washed with water. The acid base purification treatment repeated till the unknown impurity at RRT 0.47 – 0.49 is NMT 0.3%. The obtained solid after acid base treatment is treated with acetone. Raise temperature of reaction mass to 55 – 65°C and maintained for 0.5 hr. Cooled to 20 – 30°C. Stir for 0.5 hr and filter the solid and wash with acetone.
Result: Dry Wt. 160 g, HPLC: 99.8%.

Example 4: Process for the purification of (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one, Compound of Formula IV (Impurity profile, yield, process time etc..)

The Purification of (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one, Compound of Formula IV where studied by conducting experiments of using range of solvents like Ethyl acetate, Diisopropyl ether, Isopropyl acetate, Acetone, Toluene, Dichloromethane and different mixture of solvent we have performed and observed that impurity at 0.47 RRT not removed by this solvent technique.
The inventors have observed that during process of Preparation of (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of Formula IV formation of an impurity at 0.47-0.49 RRT occurs about 1.5% to 1.0%. The amount of impurity formation varies depending upon reaction conditions, amount of solvent, nature of solvent used. It is advantageous to remove impurity at this stage; otherwise it hinders the process of hydrogenation of (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV and further it gets converts to hydrochloride in the presence of hydrochloric acid, hence difficult to remove.
So, inventors have developed acid and base purification process, during acidic treatment impurity at 0.47 – 0.49 RRT removed easily by acid and base treatment.

The purity was determined by separating a sample by high performance liquid chromatography (HPLC) under the following conditions, and calculating the area percentage thereof of each peak.
HPLC Procedure:
Mobile phase: A mixture of 600volume of water, 400 volume of methanol and 1 volume of triethyl amine, adjust the pH to 3.0with orthophosphate acid and filter.
Standard Solution: 0.5mg/mL of Stage-I standard in mobile phase.
Sample solution: 0.5mg/mL of sample in mobile phase.
Chromatographic system:
Mode: LC
Detector: UV 230nm
Column: Inertsil ODS-3V (250 X 4.6mm), 5µ
Flow: 1mL/min.
Injection Volume: 20µL
Retention time of Stage-I: about 17.2min

The comparative data of crude and purified of (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV by using different solvents and acid and base treatment.

Removal of impurity at RRT 0.47 – 0.49 from (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV by using different organic solvents and is tabulated as below in table 1
Table 1:
Example Purification solvent HPLC Imp @ 0.47 - 0.49 RRT Imp @ 1.73 RRT Figure
Ex 1 Crude Material 98.409 1.176 0.171 1
Ex 5 Purification in Ethyl acetate 98.47 1.166 0.145 2
Ex 6 Purification in Diisopropyl ether 98.366 1.179 0.196 3
Ex 7 Purification in Isopropyl acetate 98.388 1.182 0.145 4

Removal of impurity at RRT 0.47 – 0.49 from (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV by using different acid base treatment and is tabulated as below Table 2 as per example 2

Table 2
Example Purification solvent HPLC Imp @ 0.47 - 0.49 RRT Imp @ 1.73 RRT Figure
Ex 2 Crude Material 96.837 1.275 0.398 5
Ex 2 Ist Acid treatment 99.466 0.232 0.301 6
Ex 2 Ist Base treatment 99.510 0.238 0.252 7
Ex 2 IInd Acid treatment 99.790 0.070 0.141 8
Ex 2 IInd Base treatment 99.799 0.068 0.132 9
Ex 2 A/Acetone slurry 99.935 0.065 ND 10

Removal of impurity at RRT 0.47 – 0.49 from (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV by using acid base treatment and is tabulated as below Table 3 as per example 3
Example Purification solvent HPLC Imp @ 0.47 - 0.49 RRT Imp @ 1.73 RRT Figure
Ex 3 Crude Material 96.320 2.607 0.230 11
Ex 3 Ist Acid treatment 99.086 0.645 0.184 12
Ex 3 Ist Base treatment 99.468 0.242 0.189 13
Ex 3 IInd Acid treatment 99.447 0.319 0.168 14
Ex 3 IInd Base treatment 99.467 0.314 0.162 15
Ex 3 A/Acetone slurry 99.737 0.203 0.015 16

Advantages of the process for the purification of (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one, Compound of Formula IV (Impurity profile, yield, process time etc..)
? Compound of Formula IV is purified by Acid and Base purification procces.
? No any organic solvent was suitable to purge the impurity at RRT 0.47 to 0.49%.
? Excellent yield is obtained by acid and base purification.

EXAMPLE 8 : Preparation of 2-((1-benzylpiperidin-4-yl) methyl)-5,6-dimethoxy- 2,3-dihydro-1H-inden-1-one Hydrochloride (Donepezil Hydrochloride) of formula I
(E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (100.0 g) was taken in methylene dichloride (500 ml) and methanol (500ml) followed by addition of 5% palladium-carbon (5 g). The reaction mixture was hydrogenated at temperature 20-30°C and 1 Kg/Cm2 pressure for 1 to 2 hours. After completion of reaction, the catalyst was filtered off and filtrate was concentrated under vacuum to obtained residue. The residue was dissolved in solution of hydrochloric acid in water. Washed with ethyl acetate and extracted with dichloromethane, followed by concentration in vacuum to obtain a crystal, which was recrystallized from methanol/ diisopropyl Ether to obtain 90 g of 2-((1-benzylpiperidin-4-yl)methyl)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one Hydrochloride having purity of 99.9% by HPLC and % Yield : 81.81%.

The inventors have observed that during process of hydrogenation of (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one to 2-((1-benzylpiperidin-4-yl)methyl)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one formation of an impurity at 0.29-0.32 RRT occurs about 10.0% to 5.0% (figure 17). The amount of impurity formation varies depending upon reaction conditions, amount of solvent, nature of solvent used. It is advantageous to remove impurity at final stage and further it gets difficult to remove.

So, inventors have developed a process of treating 2-((1-benzylpiperidin-4-yl)methyl)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one with acid and purification with ethyl acetate and Methylene Dichloride further process reaction mass is treated with Methanol and Diisopropyl Ether, during acidic treatment impurity at 0.29 – 0.32 RRT is removed easily by ethyl acetate and MDC treatment wherein the impurity is impurity at 0.29-0.32 RRT after purification process is less than 0.30%. (figure 18)

,CLAIMS:We Claim,

1. An improved process for the preparation of highly pure 2-((1-benzylpiperidin-4-yl)methyl)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one Hydrochloride (Donepezil HCl) of formula I

Formula I
comprises:
a) condensation reaction of 5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula-II with 1-benzylpiperidine-4-carbaldehyde compound of formula-III to obtain of (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV;

b) treating (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV with acid and converting to pharmaceutically acceptable salts and isolating (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one Hydrochloride compound of formula V;
c) treating the compound of formula V with base to (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV;
d) hydrogenating (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV in presence of palladium catalyst and an organic solvent;
e) treating the donepezil base with acid and converting to pharmaceutically acceptable salts.

2. The improved process as claimed in claim 1, wherein palladium catalyst is preferably Palladium oxide, Palladium on carbon.

3. The improved process as claimed in claim 1, wherein the organic solvent comprises ethers, alcohols, chlorinated hydrocarbons, esters, ketones, hydrocarbons, polar aprotic solvents, water and mixtures thereof.

4. The improved process as claimed in claim 1, wherein ketone solvent are 2-pentanone, 3-pentanone, 2-hexanone, methyl isobutyl ketone, 2-heptanone, 3-heptanone, 4-heptanone, diisobutyl ketone, mesityl oxide, phorone, 2-octanone, cyclohexanone, methylcyclohexanone, isophorone, 2,4-pentanedione or 2,5-hexanedione, acetone or methyl ethyl ketone.

5. The improved process as claimed in claim 1, wherein acid selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or boric acid.

6. The improved process as claimed in claim 1, wherein 2-((1-benzylpiperidin-4-yl)methyl)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one Hydrochloride (Donepezil HCl) of formula I is recrystallized from methanol and diisopropyl ether to obtain highly pure donepezil hydrochloride having purity greater than 99.2% preferably greater than 99.9%.

7. The improved process as claimed in claim 1, wherein condensation reaction of step (a) is conducted at 25°C-70°C in methylene dichloride for about 2-10 hours.

8. A improved process for the preparation of (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV comprises:

a) condensation reaction of 5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula-II

with 1-benzylpiperidine-4-carbaldehyde compound of formula-III;

in the presence of phase transfer catalyst and base with methylene dichloride.
b) treating (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV with acid and converting to pharmaceutically acceptable salts and isolating (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one Hydrochloride compound of formula V;
c) treating the compound of formula V with base to (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV;
d) washing with ketone solvent.

9. The improved process as claimed in claim 7, wherein phase-transfer catalyst is a quaternary ammonium salt such as tetra-n-butylammonium chloride, tetra-n-butylammonium bromide (TBAB), and methyltri-n-octylammonium chloride

10. The improved process as claimed in claim 8, wherein process for the purification of E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV to remove impurity comprising
a) treating the reaction mixture with acid wherein pH is 0.1 to 6.0;
b) treating the reaction mixture with base wherein pH is greater than 11.0;
c) repeat step (a) and step (b) up to impurity at 0.47 – 0.49 RRT NMT 0.3 %;
d) washing with ketone solvent at 55-65°C.

11. The improved process as claimed in claim 10, wherein ketone solvent are 2-pentanone, 3-pentanone, 2-hexanone, methyl isobutyl ketone, 2-heptanone, 3-heptanone, 4-heptanone, diisobutyl ketone, mesityl oxide, phorone, 2-octanone, cyclohexanone, methylcyclohexanone, isophorone, 2,4-pentanedione or 2,5-hexanedione, acetone or methyl ethyl ketone.

12. The improved process as claimed in claim 10, wherein acid selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or boric acid.

13. The improved process as claimed in claim 10, wherein base selected from sodium hydroxide and potassium hydroxide

14. A process for the preparation of 2-((1-benzylpiperidin-4-yl)methyl)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one Hydrochloride (Donepezil hydrochloride) of formula I comprises:

a) hydrogenating (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one compound of formula IV in presence of Palladium catalyst and an organic solvent;
b) treating the donepezil base with hydrochloric acid (HCl) and converting to pharmaceutically acceptable salts and dissolving in water;

c) extracting impurity at 0.29 – 0.32 RRT by washing with ethyl acetate repeat washing up to impurity at 0.29 – 0.32 RRT NLT 0.3%;
d) extracting 2-((1-benzylpiperidin-4-yl)methyl)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one Hydrochloride (Donepezil hydrochloride) of formula I with Methylene Dichloride and distilling;
e) residue of 2-((1-benzylpiperidin-4-yl)methyl)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one Hydrochloride (Donepezil hydrochloride) of formula I is crystallized with methanol and diisopropyl ether having purity greater than 99.2% to 99.9%.

15. The improved process as claimed in claim 14, wherein organic solvent comprises ethers, alcohols, chlorinated hydrocarbons, esters, ketones, hydrocarbons, polar aprotic solvents, water and mixtures thereof.

16. An isolated compound (E)-2-((1-benzylpiperidin-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one Hydrochloride compound of formula V

Dated this 30th Day of October, 2021