WO2015109377A1

WO2015109377A1 - Process for preparing donepezil hydrochloride forms i and iii; and an intermediate compound thereof

Info

Publication number: WO2015109377A1
Application number: PCT/BR2014/050022
Authority: WO
Inventors: Ogari De Castro Pacheco; Ariel Lázaro Llanes GARCIA
Original assignee: Cristália Produtos Químicos Farmacêuticos Ltda.
Priority date: 2013-11-29
Filing date: 2014-11-27
Publication date: 2015-07-30
Also published as: BR102013030928A2; AR098504A1

Abstract

The present invention relates to a new efficient and industrially feasible process for the preparation of the commercial crystalline forms of donepezil hydrochloride Form I and III, with high purity and in a selective manner. This invention also relates to a new process for preparing an intermediate compound useful in the preparation of donepezil hydrochloride.

Description

"PROCESS FOR PREPARING DONEPEZIL HYDROCHLORIDE FORMS I AND III; AND AN INTERMEDIATE COMPOUND THEREOF".

The present invention is related to the organic chemistry field. Particularly, this invention relates a new efficient and industrially feasible process for preparing commercial crystalline forms of donepezil hydrochloride Forms I and III, with high purity and in a selective manner. The present invention also relates to a new process for preparing an intermediate compound useful in the preparation of donepezil hydrochloride.

State of the art

Donepezil, chemically known as l-benzyl-4- ( 5, 6- dimethoxy-l-indanon-2-yl ) methyl ] piperidine of formula (I),

is an active pharmaceutical ingredient indicated for the treatment of senile dementia, especially Alzheimer's disease, due to its property of reversibly and selectively inhibit the acetylcholinesterase enzyme. It is administered orally and is marketed in the form of tablets containing 5 mg or 10 mg of donepezil hydrochloride.

Donepezil hydrochloride is a white crystalline powder. It is freely soluble in dichloromethane, chloroform, methanol, water and glacial acetic acid; slightly soluble in ethanol and acetonitrile ; insoluble in ethyl acetate and hexane . This compound exhibits several polymorphic or pseudopolymorphic forms reported in the state of the art.

Donepezil and its pharmaceutically acceptable salts were disclosed in the U.S. Patent No. 4,895,841. The Example 4 of this document describes a purified crystalline form of donepezil hydrochloride obtained by recrystallization from a mixture of methanol/isopropyl ether .

U.S. patent Nos . 5,985,864 and 6,140,321 describe five crystalline forms of donepezil hydrochloride, Forms I to V, and the amorphous form, and their preparation methods. The five crystalline forms were shown to be stable to heat when compared to the amorphous form, and Form I was the sole that presented hydration molecule in molar equivalent amount of about 1:1. According to these documents, the purified crystalline form of donepezil hydrochloride monohydrate is obtained, for example, by recrystallization of donepezil hydrochloride from methanol or by dissolving donepezil hydrochloride in methanol, followed by addition of diethyl ether or diisopropyl ether.

Donepezil hydrochloride Form I and III, due to their good stability, are useful in the manufacture of a medicament for the treatment of dementia. Form I is used in the preparation of medicament reference Eranz^®. Both forms are commercial and have analytical monograph described in U.S. Pharmacopeia 36.

U.S. patent application 20090137811 reports five polymorphic forms of this product: donepezil hydrochloride anhydrous, hemihydrate, monohydrate (Form I), sesquihydrate and dihydrate. The Example 21 of this document demonstrates the process for preparing Form I, wherein donepezil hydrochloride was suspended in a mixture of methanol/water and was heated to 40°C until completely dissolution. The solution obtained was filtered, cooled to 0-5°C and stirred for 10 minutes (during this time the crystallization was initiated) . Then, methyl tert-butyl ether (MTBE) was added to the mixture and was kept stirring for 15 minutes. The precipitate obtained was washed with MTBE and then dried under vacuum (10 mbar) at a temperature of 40°C for 1 hour. The overall yield for obtaining Form I was about 74.8%.

U.S. Patent 7,332,606 describes the catalytic hydrogenation of the compound l-benzyl-4- [ ( 5, 6-dimethoxy-l- indanon-2-yl ) methyl ] piperidine to obtain donepezil or its salt. In the case of catalytic hydrogenation, attention should be given to the undesirable reactions due to the four reaction sites present in the starting material. So the objective is to obtain donepezil with high purity and yield through selective hydrogenation to reduce only the double bond of exocyclic a, β-unsaturated carbonyl, avoiding simultaneous debenzylation reactions, reduction of carbonyl group and hydrogenation of the benzene ring. According to this document, undesirable reactions can be avoided by using of a palladium-alumina catalyst and appropriate choose of the reaction conditions, as well as the use of a solvent, preferably methanol, tetrahydrofuran, toluene, ethyl acetate, or a mixture thereof; reaction temperature preferably from 0°C to 25°C; and the use of hydrogen pressure in the catalytic hydrogenation preferably between 0.1 and 2 megapascal (Mpa) . This process is expensive and hazardous, since it works with hydrogen gas under high pressure, which requires investment in reactors and special reaction conditions. There are many other known methods in the prior art which also employs hydrogenation under high pressure with other catalysts such as Pd/C (US 20100105916, WO 2007/057226), Pt/C (WO 2007/108011) and Pt0₂ (US 6,649,765, US 7,446,203) to obtain donepezil or donepezil hydrochloride.

The process described in the U.S. patent application

20100105916, which uses 10% palladium on carbon along with one additive, such as thiourea in tetrahydrofuran to reduce l-benzyl-4- [ (5, 6-dimethoxy-l-indanone-2- ylidene) methyl ] piperidine to donepezil in a chemoselective manner, without concomitant hydrogenolysis reaction, did not show reproducibility when tested. Unlike reported in this document, donepezil hydrochloride was obtained with 75% yield and with about 18% relative area of the debenzylated impurity .

In general, the processes reported to obtain donepezil hydrochloride present certain disadvantages, such as several unit operations in each reaction step, the most of them require special conditions to work with gases, employ very expensive materials such as platinum or platinum oxide, hazardous reaction conditions and halogenated solvents, complex and tedious steps of treatment and purification, such as chromatography and distillation of solvents to dryness, leading to poor reproducibility in relation to the purity of the product. Consequently, the development of a new, effective, economical, safe and environmentally friendly process for preparing donepezil hydrochloride in Forms I and III is required.

SuiranarY of the Invention

The present invention relates a new efficient and industrially feasible process for preparing donepezil hydrochloride in Forms I and III, highly pure and selectively.

According to the present invention, donepezil hydrochloride in Forms I and III is obtained with high purity directly from the reaction medium, without requiring any type of purification by recrystallization or column chromatography. The products are given with HPLC purity greater than 99.8% and individual impurities less than 0.1%. The present invention also provides a new process for preparing an intermediate compound of formula (III), 5,6- dimethoxy-2- [ (piperidin-4-yl ) methyl ] indan-l-one, useful in the preparation of donepezil hydrochloride. The product is obtained with HPLC purity greater than 99.7%. The high purity of this product is essential to ensure appropriate purity to the final product, within the requirements of international pharmacopoeias and specifications for use as an active pharmaceutical ingredient.

The process of present invention employs as starting material the commercially available compound l-benzyl-4- [ (5, 6-dimethoxy-l-indanone-2-ylidene) methyl] piperidine, of formula (II) . This compound is useful for the preparation of intermediate compound of formula (III) and, subsequently, of the two commercial forms of donepezil hydrochloride, Form I of formula (V) and Form III of formula (IV), in a selective manner.

The general process for preparing of donepezil hydrochloride Forms I and III comprises the following steps according to Scheme 1 below:

Scheme 1 The general process of the present invention comprises the following steps:

1.1. Concomitant reactions of reduction of the double bond exocyclic a, β-unsaturated carbonyl and debenzylation of starting material l-benzyl-4 [ ( 5, 6-dimethoxy-l- indanone-2-ylidene ) methyl] piperidine of formula

(ID ;

1.2. Precipitation and isolation of the intermediate 5,6- dimethoxy-2- [ (piperidin-4-yl ) methyl ] indan-l-one as a hydrochloride salt of formula (III) ;

2.1. Benzylation reaction of intermediate of formula (III) to obtain donepezil;

2.2. Precipitation and isolation of donepezil as a anhydrous hydrochloride salt in Form III of formula (IV) ;

3.1. Conversion of Form III (IV) of donepezil hydrochloride in donepezil hydrochloride monohydrate Form I of formula (V) .

Description of the Figures

The description of the Figures in this report is provided to illustrate the present invention.

Figure 1: XRDP for anhydrous donepezil hydrochloride Form III .

Figure 2: DSC for anhydrous donepezil hydrochloride Form III .

Figure 3: IR Spectrum (KBr) for anhydrous donepezil hydrochloride Form III.

Figure 4: XRDP for donepezil hydrochloride monohydrate Form Figure 5: DSC for donepezil hydrochloride monohydrate Form I .

Figure 6: IR Spectrum (KBr) for donepezil hydrochloride monohydrate Form I . Detailed description of the invention

In a first embodiment, the present invention relates a process for preparing donepezil hydrochloride hydrate, Form I, represented by formula (V) :

comprising the following steps:

(a) Concomitant reactions of reduction of the double bond exocyclic a, β-unsaturated carbonyl and debenzylation of the compound l-benzyl-4- [ ( 5, 6- dimethoxy-l-indanone-2-ylidene ) methyl ] piperidine represented by formula (II) :

in the presence of 10% palladium on carbon metal catalyst and a hydrogen transfer agent, in a suitable organic solvent, or mixture of an organic solvent with water, at a temperature of 53-63°C; followed by treating the reaction medium with concentrated hydrochloric acid to obtain the intermediate 5, 6-dimethoxy-2- [ (piperidin-4- yl) methyl] indan-l-one hydrochloride represented by formula (III);

Benzylation reaction of the intermediate of formula (III) with a benzyl derivative represented by the formula VI) :

wherein X represents a leaving group selected from the group consisting of chloride, bromide, iodide, mesylate and tosylate; in the presence of a base and a phase transfer catalyst, in a heterogeneous mixture of solvents consisting of water and dialkyl ether at a ratio ranging from 1:1 to 1:10, at a temperature ranging from 30°C to 80°C, obtaining free base donepezil, which is dissolved in ethyl acetate or isopropyl followed by treating the solution with concentrated hydrochloric acid to obtain the donepezil hydrochloride, Form III, represented by formula (IV) :

Conversion of the donepezil hydrochloride Form III in donepezil hydrochloride monohydrate Form I by dissolving donepezil hydrochloride in 3-6 parts of methanol having from 2% to 20% water, at a temperature between 40°C and 65°C, followed by cooling the hydroalcoholic solution at room temperature, and slow addition of the solution, under stirring, at 15-25 parts of antisolvent ethyl tert-butyl ether at temperature between 0°C and 12°C.

In a second embodiment, the present invention relates to a process for preparing of donepezil hydrochloride, Form III, represented by formula (IV) :

comprising the steps (a) and (b) as defined above.

In a third embodiment, the present invention relates to a process for the preparation of intermediate 5, 6- dimethoxy-2- [ (piperidin-4-yl ) methyl ] indan-l-one

hydrochloride represented by the formula (III ) :

comprising the step (a) as defined above.

The first step of the process of present invention, involving concomitant reactions of reduction of the double bond exocyclic a, β-unsaturated carbonyl and of debenzylation of l-benzyl-4- [ ( 5, 6-dimethoxy-l-indanone-2- ylidene) methyl] piperidine. This step is performed in the presence of a metal catalyst by using a hydrogen transfer agent, in a suitable organic solvent or its mixtures with water in different ratios, in an appropriate reaction time (Scheme 2 ) .

Scheme 2

The metal catalyst is preferably 10% palladium on carbon stabilized with about 50-60% humidity.

The hydrogen transfer agent is selected from the group consisting of formic acid, ammonium formate, hydrazine and ammonium hypophosphite . The hydrogen transfer agent is preferably formic acid or ammonium formate; more preferably formic acid.

The organic solvent is selected from the group consisting of a short hydrocarbon chain alcohol, such as methanol, ethanol, Ώ-propanol, isopropanol, Ώ-butanol and 2-butanol; an ether such as dibutyl ether, methyl tert- butyl ether, ethyl tert-butyl ether, tetrahydrofuran, 1,4- dioxane, 1 , 2-dimethoxyethane, and diglyme; an ester, such as ethyl acetate and isopropyl acetate; an amide, such as N,N- dimethylformamide, N, N-dimethylacetamide and N- methylpyrrolidone ; a halogenated hydrocarbon, such as dichloromethane, chloroform and dichloroethane ; a hydrocarbon, such as toluene, xylene, hexane, heptane and cyclohexane; an organic acid, such as acetic acid and propionic acid; its mixtures and mixtures thereof with water in different ratios. Preferably, the organic solvent is methanol, ethanol or isopropanol; more preferably isopropanol . The reaction is performed in a temperature range of 53-63°C; preferably of 56-60°C. The inventors have observed that temperatures lower than 56°C make very slow the reaction kinetic, resulting in increase of the reaction time, which leads the competition of side reactions. On the other hand, temperatures over 60 °C lead to formation of impurities, possibly due to the competitive reactions of super-reduction .

The reaction time is between 0.25 h and 5.0 h, depending on the scale and the reaction conditions used. Preferably the reaction time is between 0.8 h and 1.5 h, more preferably between 1.0 h and 1.3 h for the reaction conditions optimized for industrial scale. The inventors have observed that prolonged reaction time leads to formation of traces of different impurities, which increase as a function of exposure time of the product to catalytic reduction conditions, inclusive at room temperature.

The 10% palladium on carbon catalyst stabilized with about 50-60% water, was selected for the process of present invention due to its high industrial applicability, lower cost and ability to promote efficiently the hydrogenolysis reaction of the benzyl group and the reduction reaction of double bond exocyclic a, β-unsaturated carbonyl compared with 10% platinum on carbon catalyst and platinum oxide (Adam's catalyst) . Furthermore, the lower activity of the 10% palladium on carbon catalyst in relation to, for example, Pearlman catalysts (20% palladium hydroxide on carbon) , Raney Nickel or 5% rhodium on carbon, avoids the appearance of by-products by competitive super-reduction reactions.

The amount of 10% palladium on carbon catalyst employed is between 1.0 mol% and 3.0 mol%; preferably between 1.6 mol% and 2.3 mol%; more preferably between 1.8 mol% and 2.0 mol%. High amounts of 10% palladium on carbon catalyst lead to much faster reactions, with quantitative conversion, but less economical and more likely to form persistent impurities. Small amounts of catalyst lead to incomplete or slow reaction kinetics.

According to present invention, the transfer of hydrogen atoms to the substrate from the reagent donor, during the hydrogenolysis and catalytic reduction reactions, results surprisingly in a fast and efficient process when compared to hydrogenation using hydrogen gas. This allows the use of small amounts of palladium metal catalyst when compared with the processes for the production of donepezil hydrochloride of prior art, brings safety and flexibility to the process and decreases operational costs, since hydrogen gas is not used and does not require special reactor, stirring or technology to manipulate gases. In addition, the sources of hydrogen used in the process of the present invention are cheap and do not have problems of specific residue. Also, the intermediary of reaction, 5, 6-dimethoxy-2- [ (piperidin-4- yl) methyl] indan-l-one hydrochloride of formula (III), is obtained with excellent yield (88-93%) and with high purity (> 99.7%) directly from the reaction medium. The high purity of this intermediate is important to ensure proper purity to the final product, within requirements of international pharmacopoeias and within specifications for use as active pharmaceutical ingredient.

Among the hydrogen transfer agents tested, formic acid is what presents the best results, taking into account its low cost, ease operation, yield and purity obtained for the intermediate 5, 6-dimetoxi-2- [ (piperidin-4-il ) metil ] indan- 1-ona hydrochloride of formula (III) .

The transfer of hydrogen atoms with ammonium formate also works well at temperatures of 56-60°C. However, ammonium formate has the disadvantage of sublimating when heated, and the yield and purity obtained for the intermediate of formula ( I I I ) are slightly lower than those obtained with the use of formic acid.

The amount of hydrogen transfer agent used is between

2.5 and 12.0 equivalents; preferably between 3.0 and 5.0 equivalents; more preferably between 3.0 and 3.5 equivalents .

The selection of isopropanol as reaction solvent occurred because it was superior to the use of other solvents. For example, using ethyl acetate as single reaction solvent was verified coexistence of a product mixture after 6 h of process due to an incomplete hydrogenolysis reaction. On the other hand, isopropanol provides operational safety greater than, for example, methanol and ethanol due to its lower vapor pressure. The use of isopropanol also avoids the tedious treatment of the reaction mixture, when methanol/water or ethanol/water mixtures are required. Another advantage on using isopropanol as the reaction solvent is the low solubility of the starting material of formula (II) and high solubility of the reaction product of formula (III), in the free base form, in this solvent. This difference in solubility allows, firstly, visual monitoring of the process progress and, secondly, the removal of traces of unreacted starting material through of a centrifugation or filtration operation. Also, the use of isopropanol allows direct precipitation of the reaction product in the form of its hydrochloride salt with purity greater than 99.7%, by treatment of reaction medium with concentrated hydrochloric acid, since of 5, 6-dimethoxy-2- [ (piperidin-4- yl ) methyl ] indan-l-one hydrochloride of formula (III) is not soluble in isopropanol. Finally, using isopropanol as reaction solvent eliminates the possibility of by-product formation due to a possible reductive methylation of the nitrogen from intermediate of formula (III), as might happen by employing methanol as solvent, in a variant of the Eschweiler-Clarke reaction, since formaldehyde is readily formed from methanol in the presence of 10% palladium on carbon and air.

The second step of the process of the present invention involves the benzylation reaction of 5, 6- dimethoxy-2- [ (piperidin-4-yl ) methyl ] indan-l-one hydrochloride of formula (III) - (Scheme 3) .

Scheme 3

This reaction is carried out in a heterogeneous mixture of solvents, using a benzyl derivative of formula (VI) in the presence of a base and a phase transfer catalyst (PTC) .

The group X of formula (VI) represents a leaving group selected from the group consisting of chloride, bromide, iodide, tosylate, and mesylate. The benzyl derivative is preferably chloride or bromide. The amount of benzyl derivative used is between 0.95 equivalents and 1.25 equivalents; preferably between 0.98 equivalents and 1.10 equivalents; more preferably between 1.00 equivalent and 1.06 equivalents. The addition of the benzyl derivative in the reaction medium can be made in the temperature between 5°C and 65°C; preferably in the temperature range between 15°C and 60°C; more preferably in the temperature range between 15°C and 35°C.

The base is selected from the group consisting of a tertiary amine, alkali metal bicarbonate, alkali metal carbonate and mixtures thereof. Examples of tertiary amines include triethylamine, diisopropylethylamine, N- methylmorpholine, N-methylpiperidine, N,N- dimethylbenzylamine, pyridine, 2-methylpyridine, 3- methylpyridine, 4-methylpyridine, 2 , 4-lutidine, 2,6- lutidine, and triethanolamine . Examples of alkali metal bicarbonates include sodium bicarbonate and potassium bicarbonate. Examples of alkali metal carbonates include lithium carbonate, sodium carbonate and potassium carbonate. The base is preferably sodium carbonate or potassium carbonate; more preferably potassium carbonate. The amount of base used is between 200 mol% and 600 mol%; preferably from 200 mol% to 300 mol%; most preferably from 200 mol% to 250 mol%. The amount of base smaller than 200 mol%, such as 105 mol% or 55 mol% leads to an incomplete reaction, with a high content of donepezil benzyl bromide quaternization by-product of formula (VII) .

The phase transfer catalyst (PTC) is selected from the group consisting of a quaternary ammonium salt, a quaternary phosphonium salt, a crown ether and a polyether. Examples of quaternary ammonium salts include iodide, bromide, chloride or hydrogen sulphate of: tetramethylammonium, tetraethylammonium, tetrapropylammonium, tetrabutylammonium, tetrapentylammonium, tetrahexylammonium, tetraheptylammonium,

tetraoctylammonium, tetrahexyldecylammonium,

tetraoctyldecylammonium, tetradecyltrimethylammonium, hexadecyltrimethylammonium, octadecyltrimethilammonium, tert-butyletyldimethilammonium, benzyltrimethylammonium, 1- methylpyridinium, 1-hexadecylpyridinium and 1,4- diethylpyridinium. Examples of quaternary phosphonium salts include tributyl (methyl ) phosphonium iodide, triethyl (methyl ) phosphonium iodide, methyltriphenoxyphosphonium iodide, tetrabutylphosphonium bromide, benzyltriphenylphosphonium bromide and tetraphenylphosphonium chloride. Exemple of crown ethers include 18-crown-6, dibenzo-18-crown-6, dicyclohexano-18- crown-6 and 15-crown-5. Examples of polyethers include polyethylene glycols of different sizes. The phase transfer catalyst is preferably a quaternary ammonium salt; more preferably tetrabutylammonium bromide. The amount of the phase transfer catalyst used is between 1 mol% and 25 mol%; preferably between 2.5 mol% and 10 mol%; more preferably from 4 mol% to 6 mol%.

The benzylation reaction temperature is between 30°C and 80°C; preferably between 45°C and 65°C; more preferably between 50°C and 60°C.

The heterogeneous mixture of solvents consists of water and dialkyl ether such as methyl tert-butyl ether, ethyl tert-butyl ether and dibutyl ether or mixture thereof. The organic solvent is preferably methyl tert- butyl ether or ethyl tert-butyl ether; most preferably ethyl tert-butyl ether. The water/dialkyl ether ratio is between 1.0:1.0 to 1.0:10.0; preferably between 1.0:1.0 and 1.0:3.0; more preferably between 1.0:1.0 and 1.0:1.3. The inventors have observed that the nature of the solvent has an important role in the control of the product of reaction. Biphasic mixtures of water with other organic solvents, for example, ethyl acetate or isopropyl ethyl originate preferably the donepezil benzyl bromide quaternization by-product of formula (VI I ) . Therefore, the use of mixtures water/ester in this step of the process is not appropriate.

On the other hand, the use of simple reaction solvents in this step of the process, such as acetones, acetonitrile, ethyl acetate and dicloromethane provides low yield of the donepezil hydrochloride.

The patent application WO 2004082685 describes the use of biphase system water/halogenated hydrocarbon. Although this system has worked when tested for the benzylation reaction, in practice it presents some disadvantages if compared with the system water/dialkyl ether, such as: 1) using of halogenated solvents that are environmentally incorrect and with high toxicity is not recommended for industrial scale; 2) sensitive reaction to increase of reaction temperature above 25°C, leading to formation of several impurities; 3) lower starting material conversion into reaction product in the time described of 0.5 h (92- 93% in 0.5 h, being necessary at least 2.5 h for a 97-98% conversion); 4) high formation of donepezil benzyl bromide quaternization by-product (9-11%); 5) tedious treatment of the reaction medium, with unit operations less appropriated to reactions in large scale; 6) low purity of the reaction product and high amount of individual impurities.

The patent application WO 2007057226 describes the use of the heterogeneous water/aromatic hydrocarbon system, specifically toluene. The process described does not use phase transfer catalysts and uses, preferably, sodium bycarbonate as base and benzyl hydrochloride as benzylation agent. Among the deficiencies found, we can list: 1) high reaction temperature and reaction times higher than those used in the present invention, being 145°C and 8 h, respectively; 2) Use of improper unit operations for industrial scale, for example, toluene concentration to the dryness; 3) Addition of ethyl acetate over the residue after the evaporation of the toluene must be slow, approximately 4 h of addition, to obtain a good purification/extraction; 4) The mixture obtained has to remain over 12 h under stirring at room temperature before the filtration of the donepezil benzyl bromide quaternization by-product; 5) Need of a temperature of -8°C for the precipitation of the donepezil hydrochloride; According to the present invention, once concluded the benzylation reaction the mixture was diluted with water and the organic solvent was distilled using or not reduced pressure, preferably using reduced pressure. The mixture was cooled down to room temperature, the solid was vacuum filtrated or centrifuged, washed with water and allowed to flow sufficiently. The solid can be dried or alternately dissolved preferably in ethyl acetate or isopropyl acetate to temperature between 20°C and 60°C; preferably between 30°C and 60°C; more preferably between 45°C and 60°C. The mixture is cooled to room temperature and vacuum filtered through Celite, removing the donepezil benzyl bromide quaternization by-product of formula (VI I ) , which is insoluble in ethyl acetate and in isopropyl acetate. The organic phase can optionally be washed with water and can optionally be treated with active charcoal. However, it was verified that there is no need of the treating of the product solution in ethyl acetate or isopropyl acetate with activated charcoal. The product donepezile was precipitated directly from the reaction medium in hydrochloride salt, by treatment of the solution of ethyl acetate or isopropyl acetate with concentrated hydrochloric acid, at the temperature between 10°C and 80°C; preferably between 20°C and 70°C; more preferably between 65°C and 70°C. The mixture is cooled between 5°C and 35°C. The product, essentially pure, was vacuum filtered or centrifuged, and washed and macerated with ethyl acetate or isopropyl acetate. The donepezil hydrochloride was dried at a temperature between 35-45°C, obtaining the Form III. According to the present invention, reaction times between 3.5 h and 7.0 h have proved to be optimum to the reaction in industrial scale. The inventors have observed that long reaction times, for example, 24 h, leads to the formation of traces of impurities. However, a short and enough time for the reaction, such as, 3.5 h, has provided donepezil hydrochloride, Form III, with a HPLC purity higher than 99.8% and individual impurities lower than 0.1% in relative areas.

According to one aspect of the present invention, during the benzylation reaction it was obtained only 4-6% of relative mass of donepezil benzyl bromide of formula (VII), that represents an approximate consumption of only 3% of the starting material in this side reaction. According to the invention, the by-product of formula (VII) was the major impurity of process and it was totally eliminated during the operations of treatment of the reaction medium.

According to other aspect of the present invention, the donezepil was isolated with good yield (78-84%) directly from the reaction medium in the form of anhydrous donepezil hydrochloride, Form III, with purity above 99.8% and individual impurities below 0.1%, without the need of any type of chromatographic purification or recrystallization.

According to the process of the present invention, the anhydrous donepezil hydrochloride, Form III, was obtained with 72%-78% of overall yield.

According to the process of the present invention, the reduction/debenzylation strategy of the starting material of formula (II) with a hydrogen transfer agent, followed by the benzylation reaction of the intermediate of formula (III) to afford donepezil hydrochloride has the benefits of higher operational easiness, avoiding the need of chemo- selective control of hydrogenation reaction. This allow the use of 10% palladium on carbon catalyst instead of expensive and selective catalysts such as 10% platinum on carbon or platinum oxide catalysts. Such strategy also eliminates the use of pressurized reactors and, consequently, the formation of several super-reduction by^¬ products obtained by methods reported in the prior art. Still, the non-desired debenzyldonepezil residue of formula (III) is minimized to a content lower than 0.05% in the final product.

The third step of the process of the present invention involves the conversion of donepezil hydrochloride, Form III, in donepezil hydrochloride monohydrated, Form I (Scheme 4) .

Scheme 4

According to the present invention, the donepezil hydrochloride Form III was dissolved in 3-6 parts of methanol containing from 2% to 20% of water; preferably in 4-5 parts of methanol containing from 3% to 6% of water; more preferably in 4-5 parts of methanol containing from 3.5% to 5.5% of water. The dissolution process was carried out at a temperature between 40°C and 65°C; preferably between 45°C and 60°C; more preferably between 50°C and 55°C. Once obtained the dissolution of the compound, the heating was turned off and the mixture was cooled at room temperature; preferably, between 20°C and 35°C. The hydroalcoholic solution obtained was slowly added over 10- 30 parts of antisolvent ethyl- tert-butyl ether; more preferably over 15-25 parts of ethyl- ert-butyl ether strongly stirred and cooled between 0°C and 12°C; preferably cooled between 5°C and 10°C; with or without crystals of donepezil hydrochloride Form I (seeds) . The mixture was stirred for 0.5 h to 1.0 h, at a temperature between 5°C and 10°C. The solid was isolated by filtration or centrifugation . The solid was washed with ethyl- tert- butyl ether and immediately was dried at a temperature between 30°C and 40°C.

According to the U.S. patent 6,140,321, the donepezil hydrochloride monohydrated, Form I, can be obtained by dissolution of the donepezil hydrochloride in methanol, cooling of the solution, followed by adding of antisolvent such as diethyl ether, disopropyl ether, methyl- ert-butyl ether, ethyl acetate or hexane on the methanolic solution. Among the disadvantages of the reported method we can mention the lower reproducibility with the use of antisolvents ethyl acetate, hexane and diethyl ether, being obtained the polymorph Form III or polymorphic mixtures instead of the desired polymorph Form I. On the other hand, the use of diethyl ether is inappropriate for production in large scale (flame point -45°C) . Another solvent of limited use in large scale is the diisopropyl ether. The last solvent is particularly dangerous, since the presence of two tertiary carbon atoms in the molecule increases the tendency to autoxidation to hydroperoxides, which polymerize to form a highly explosive crystalline solid. By other hand, attempts to reproduce the formation conditions of donepezil hydrochloride Form I according to the exposed methodology in document WO 2007/072087, which uses as antisolvent methyl- ert-butyl ether at a temperature between 5°C and 10°C, have led to the mixture of Forms I and III; even seeding the antisolvent with crystals of donepezil hydrochloride Form I, before the adding of hydromethanolic solution over the antisolvent. This demonstrates the low reproducibility of the exposed method by the authors . Particularly, one of the advantages of the process for the preparation of donepezil hydrochloride monohydrated Form I reported in the present invention, is the use of the ethyl- ert-butyl ether as precipitating agent. This antisolvent allows to afford Form I in a reproductive way, without the need to seed the crystals of Form I, whenever the conditions described (slow adding of hydromethanoic solution over the antisolvent and temperatures of precipitation of 0-12°C) are respected. Besides, the ethyl- tert-butyl is an ether that can be used safely at industrial level, with low tendency to formation of peroxides or hydroperoxides. The Form I obtained by this route presented an excellent filtration, low inorganic residue (< 0.1%) and low residue of solvents (ethyl tert- butyl ether < 2,000 ppm; ethyl acetate < 5 ppm; methanol < 50 ppm) .

According to the present invention, the donepezil hydrochloride monohydrated, Form I, was obtained with purity above of 99.8% and with overall yield of 66-72%. In summary, the process of this invention presents several advantages when compared to the processes reported in the art, such as:

1. Fast and efficient process;

2. Reproducible process;

3. Higher operational simplicity, due to the reduced number of unit operations;

4. Higher operational safety, since it does not work with high pressures nor with pressurized hydrogen gas;

5. It is not required investment in special reactors or special technology that allows to work under pressure and handling of hydrogen gas at industrial level;

6. Economic process at commercial scale, once it is not necessary the use of highly expensive metal catalysts as platinum or platinum oxide, besides to be used a minimum amount of 10% palladium on carbon catalyst.

7. The process uses environmentally friendly solvents, avoiding the use of halogenated solvents;

8. Lower generation of effluents;

9. The product is obtained with a purity level higher than 99.8% and with individual impurities less than 0.1% directly from the reaction medium, without the need of any kind of purification by recrystallization or chromatographic column. Such advantages make the invention process an economically viable and environmentally friendly process.

The following examples are merely illustrative, should be applied for a better understanding of the present invention, but should not be used with the intention of limiting the scope of the present invention.

Example 1

Synthesis of 5 , 6-dimethoxy-2- [ (piperidine-4-yl) methyl] indan-l-one hydrochloride in laboratorial scale. In a three-port glass reactor and 3 L of capacity, with magnetic stirring, thermometer and reflow condensator with open outlet for gases, were added 100 g of l-benzyl-4- [ (5, 6-dimethoxy-l-indanon-2-ylidin) methyl ] piperidine of formula (II) in 1.5 L of isoprapanol. Following, were added 12 g of 10% palladium on carbon, stabilized with 56.5% of water. Additional, 0.2 L of isopropanol were used to drag the residue of 10% palladium on carbon. The stirring was turned on to suitable speed to avoid spreading of 10% palladium on carbon to the reactor walls. Temperature controllers were adjusted for the reaction mixture to reach the temperature of 58±2°C. Once the suspension temperature reached 45-50°C were slowly added 37 mL of 85% formic acid dissolved in 0.2 L of isopropanol. The new mixture was stirred at a temperature of 58±2°C for 70 minutes. The mixture was cooled at room temperature and the stirring was stopped. The mixture was vacuum filtrated, under inert atmosphere, through Celite. The filter was washed with 0.2 L of isopropanol and this volume was added to the first filtrate. The filtrate was cooled at a temperature of 10- 20°C and, under constant stirring, was acidified with 28 mL of concentrated hydrochloric acid. The suspension was stirred during 30 minutes at a temperature of 10-20°C. The solid was vacuum filtered and washed with 0.2 L of acetone. The solid obtained was oven-dried at a temperature of 45- 50°C. 79.81 g (92.46%) of 5, 6-dimethoxy-2-piperidine-4- yl ) methyl ] indan-l-one hydrochloride of formula (III) was obtained with 99.73% of HPLC purity, in the form of a crystalline white solid. M.P. (DSC: 25-300°C, 10°C/min, N₂ 80 mL/min) = Onset in 254.64°C, Peak in 257.95°C and Enset in 260.13°C (with decomposition) .

KF = 0.51% humidity. IR (KBr, cnf¹) = broadband with center in 3435, 2930, 2799, 2716, 2633, 2573, 2509, 2463, 1686, 1595, 1501, 1462, 1314, 1265, 1217, 1113, 1034, 968, 860, 791, 565, 463, .

RMN^H (500 MHz, D₂0, TMS, t.a, ppm) δ: 6.68 (s, 1H) ; 6.60 (s, 1H) ; 3.79 (s, 3H) ; 3.71 (s, 3H) ; 3.55 (t, J = 14.0 Hz,

2H) ; 3.10 (t, J = 12.3 Hz, 2H) ; 2.91 (dd, J = 16.7 Hz and

6.3 Hz, 1H) ; 2.38 (d, J = 17.5 Hz, 1H) ; 2.34 (m, 1H) ; 2.05

(d, J = 13.8 Hz, 1H) ; 1.96 (d, J = 13.8 Hz, 1H) ; 1,79 (m,

1H) ; 1.68 (ap. t, J = 10.0 Hz, 1H) ; 1.52 (m, 1H) ; 1.44 (m, 1H) ; 1.26-1.16 (m, 1H) .

RMN-¹³C (125 MHz, D₂0, TMS, r.t., ppm) δ: 213.7; 158.2; 153.9; 151.0; 130.1; 110.2; 106.0; 58.7; 58.1; 47.6; 46.8; 39.8; 35.4; 34.4; 31.8; 30.4.

HRMS (TOF MS ES+) = Calculated for [C17H23NO3 + H]⁺ = 290.17507; found = 290.1751.

Example 2

Synthesis of 5 , 6-dimethoxy-2- [ (piperidine-4-yl) methyl ] indan-l-one hydrochloride in industrial scale.

In a reactor of 1,700 L, with mechanic stirring, heating system with control of temperature, nitrogenation system and reflow condensator with open outlet for gases, was added 830 L of isopropanol and 50 Kg of l-benzyl-4- [ (5, 6-dimethoxy-l-indanone-2-ylidin) methyl ] piperidine of formula ( I I ) . The nitrogenation system was turned on. The temperature controllers were adjusted for the mixture to reach a temperature of 58±2°C. The stirring was turned off. 6 Kg of 10% palladium on carbon (stabilized with 56.5% of water) suspended in 20 L of isopropanol were added. The stirring was turned on again and the nitrogenation system was turned off. There 18.5 L of formic acid 85% dissolved in 100 L of isopropanol were slowly added. The new mixture was stirred at a temperature of 58±2°C for 70 minutes. The heating system was turned off. The nitrogenation system was turned on again and the mixture was cooled at room temperature. The mixture was filtered through Celite under nitrogen atmosphere. The filter was washed with 100 L of isopropanol and this volume was added to the first filtrate. The filtrate was washed with 10 L of water to order to wet the residue of 10% palladium on carbon and this water was discarded. The filtrate isopropanol solution was cooled at a temperature of 10-20°C and, under constant stirring, was acidified with 14 L of concentrated hydrochloric acid. The suspension obtained was stirred for 30 minutes at 10-20°C. The solid was centrifuged and washed with 100 L of acetone. The obtained solid was oven-dried at 45°C until loss on drying < 1.0% (loss on drying: 0.2%) . 39.236 Kg (90.91%) of 5, 6-dimethoxy-2- (piperidin-4- ylmethyl ) indan-l-one of formula (III) hydrochloride were obtained, with 99.72% of HPLC purity, in the form of a white crystalline solid.

Examples 3, 4, 5 and 6

Synthesis of donezepil hydrochloride Form III in laboratory scale .

In a three-port glass reactor and 1 L of capacity, with magnetic stirring and thermometer were added 60 g of 5, 6-dimethoxy-2- (piperidin-4-ylmethyl ) indan-l-one of hydrochloride formula ( I I I ) , 3-6 g of tetrabutylammonium bromide (TBAB, see Table 1) and 53.4 g of solid potassium carbonate. Further, 300 mL of water were added and the mixture was stirred for 15 minutes. 300 mL of ethyl tert- butyl ether were added (ETBE) . 22.2 L of benzyl bromide dissolved in 60 mL of ethyl tert-butyl ether were slowly added, such that the temperature did not exceed 35°C. Then, the mixture was heated to the temperature of 55±5°C for 3.5-7.0 h (see Table 1) . Once the reaction was completed, 150 mL of water were further added. Ethyl tert-butyl ether was vacuum distilled, keeping the temperature at 50±5°C. Once the distillation was completed, the heating was turned off and the mixture was cooled to room temperature. The solid was vacuum filtered and washed with 300 mL of water, leaving it flow off sufficiently. The solid was dissolved in 450 mL of ethyl acetate at 45-55°C. The mixture was kept under stirring for 30 minutes at a temperature of 40-50°C. Heating was turned off and the mixture was cooled to room temperature. The remaining solid part was vacuum filtered with a Celite and washed with 300 mL of ethyl acetate (This solid corresponds to the major reaction impurity, identified as donepezil benzyl bromide (VII) ) . The filtrate was united and the organic phase was washed with 300 mL of water for 20 minutes. The phases were separated and the organic phase was treat or not (see Table 1) with 20 g of anhydrous sodium sulphate (Na₂S0₄) for 30 minutes. The mixture was vacuum filtered through Celite. The mass was washed with further 40 mL of ethyl acetate. The filtered was treated with 18 mL of concentrated hydrochloric acid at room temperature. The mixture was heated at 65-70°C and kept under stirring for 1 h. The heating was turned off, the mixture was cooled to 10±5°C and was kept under stirring for 30 minutes. The solid was vacuum filtered and was macerated with 360 mL of ethyl acetate at room temperature for 30 minutes. Then, the solid was vacuum filtered and dried at 40±5°C in the air recirculating oven. The anhydrous donepezil hydrochloride, Form III, formula (IV), was obtained in the form of a white crystalline solid, with yield and purity as presented in the Table 1 below : Table 1

DRXP for anhydrous donepezil hydrochloride Form III (Figure 1) .

Analysis Conditions: Start Position 2Θ = 0.0°; End Position 2Θ = 60.0°; Step Size 2Θ = 0.02; Scan Type: Coupled Two Theta/Theta; Scan Mode: Continuous PSD Fast; Temperature: 25°C; Anode: Cu Κ_αι 1.54060; Current: 10 mA; Voltage: 30 KV; 300 W; Detector: Lynx Eye; Time: 0.1 s; Steps: 2965; Variable Rotate (/min) = 1.0.

M.P. (DSC: 25-300°C, 10°C/min, N₂ 80 mL/min) : Onset in 228.64°C, Peak in 230.51°C and Onset in 233.76°C. (Figure 2)

IR (KBr, cnf¹) = broadband with center in 3435, 3053, 3001, 2926, 2841, 2461, 2417, 1693, 1595, 1497, 1458, 1367, 1308, 1261, 1219, 1119, 1074, 1034, 966, 860, 750, 700, 644, 557, 474, (Figure 3) . RMN- H (500 MHz, CDCI3, TMS, rotamers, r.t., ppm) δ: 12.41- 12.26 (ap. m, 1H) ; 7.72 (m, 1H) ; 7.63 (m, 1H) ; 7.45 (m, 3H) ; 7.16 (s, 0,5H) ; 7.11 (s, 0.5H) ; 6.89 (s, 0.5H) ; 6.85 (s, 0.5H) ; 4.20 (d, J = 6.0 Hz, 1H) ; 4.16 (ap. t, J = 6.0 Hz, 1H) ; 3.98 (s, 1.5H) ; 3,96 (s, 1.5H) ; 3.91 (s, 1.5H) ; 3.90 (s, 1.5H) ; 3.51 (d, J = 11.7 Hz, 0.5H) ; 3.45 (d, J = 11.2 Hz, 0.5H) ; 3.36-3.23 (m, 2H) ; 3.08-2.93 (m, 1H) ; 2.73- 2.60 (m, 3H) ; 2.37-2.26 (m, 1H) ; 2.18-1.89 (m, 4H) ; 1.89- 1.76 (m, 1H) ; 1.76-1.56 (2m, 1H) ; 1.56-1.41 (m, 1H) . RMN-¹³C (125 MHz, CDC1₃, TMS, rotamers, t.a, ppm) δ: 206.8; 206.6; 155.8; 149.7; 148.64; 148.57; 131.6; 131.2; 130.1; 129.4; 129.3; 129.0; 128.3; 107.5; 104.4; 60.9; 56.3; 56.1; 52.5; 52.3; 48.4; 48.1; 45.3; 44.4; 38.2; 34.0; 32.7; 32.3; 29.5; 29.4; 28.6; 26.8; 24.8. HRMS (TOF MS ES+) = Calculated for [C₂₄H₂₉NO₃ + H]⁺ = 380.22202; found = 380.2346.

Example 7

Synthesis of donezepil hydrochloride Form III in industrial scale . In a 500 L reactor, with mechanic stirring and heating system with temperature control were added 60 L of potable water and 12 Kg of 5, 6-dimethoxy-2- [ (piperidin-4- yl ) methyl ] indan-l-one hydrochloride of formula (III) . The stirring was turned on. 0.6 Kg of tetrabutylammonium bromide and 10.68 Kg of solid potassium carbonate were added. The mixture was stirred for 15 minutes and 60 L of ethyl tert-butyl ether were added. Then, 4.6 L of benzyl bromide dissolved in 12 L of ethyl tert-butyl ether were slowly added, in a way that the temperature did not exceed 35°C. The mixture was heated to the temperature of 55±5°C for 5 h. Once the reaction was completed, 30 L of water were added and the reactor was adapted to operate in vacuum distillation mode. Then, ethyl tert-butyl ether was vacuum distilled, keeping the temperature at 50±5°C. Once the distillation was completed, the heating was turned off and the mixture was cooled to 25±5°C. Vacuum system was turned off. The solid was centrifuged and washed with 60 L of water, leaving it flow off sufficiently. The solid was oven-dried at 40-45°C. The solid was dissolved in 90 L of ethyl acetate at 50-60°C and the mixture was kept under stirring for 30 minutes. The heating was turned off and the mixture was cooled to 25±5°C. The remaining solid part was filtered with a Celite and washed with 60 L of ethyl acetate (This solid corresponds to the major reaction impurity, identified as donepezil benzyl bromide quaternization by-product (VII) ) . The filtrate was united and the organic phase was washed with 60 L of water for 20 minutes. The phases were separated and the organic phase was treated with Celite for 30 minutes. The organic phase was acidified with a 3.6 L solution of concentrated hydrochloric acid in 8 L of ethyl acetate at room temperature. The mixture was heated at 65-70°C, kept under stirring at this temperature for 1 h, and then heating was turned off. The mixture was cooled to 10±5°C and kept under stirring for 30 minutes. The solid was centrifuged. It was macerated with 72 L of ethyl acetate at room temperature for 30 minutes. The solid was centrifuged and dried at 40±5°C in the air recirculating oven. 12.055 Kg (78.7%) of anhydrous donepezil hydrochloride Form III of formula (IV) were obtained, in the form of a white crystalline solid, with 99.93% of purity per HPLC, 0.04% of individual impurity and 0.25% of humidity determined by Karl Fischer (KF) .

Example 8

Synthesis of donezepil hydrochloride mono hydrated Form III in laboratory scale. In a 100 mL reactor, with magnetic stirring, thermometer and reflux condenser, it was dissolved 10 g of anhydrous donepezil hydrochloride Form III, formula (IV), in a mixture of 38.4 mL of methanol and 1.6 mL of deionized water at a temperature of 50-55°C. Once the dissolution was obtained, the heating was turned off and the solution was cooled to 25±5°C. The solution was slowly added and under strong stirring on 200 mL of ethyl tert-butyl ether cooled to 5-10°C. The mixture was stirred for 30 minutes between 5 and 10°C and the solid obtained was vacuum filtered. It was washed with 12 L of ethyl tert-butyl ether and was dried in air recirculating oven at 35-40°C. 9.682 g of donepezil hydrochloride monohydrated Form I of formula (V) were obtained, in the form of a white crystalline solid, with 99.91% of HPLC purity, 0.05% of individual impurity and 5.46% of humidity determined by Karl Fischer (KF) .

DRXP for donepezil hydrochloride monohydrated, Form I (Figure 4) .

Analysis Conditions: Start Position 2Θ = 0.0°; End Position 2Θ = 60.0°; Step Size 2Θ = 0.02; Scan Type: Coupled Two Theta/Theta; Scan Mode: Continuous PSD Fast; Temperature: 25°C; Anode: Cu K_ai 1.54060; Current: 10 mA; Voltage: 30 KV; 300 W; Detector: Lynx Eye; Time: 0.1 s; Steps: 2965; Variable Rotate (/min) = 1.0. M.P. (DSC: 25-300°C, 10°C/min, N₂ 80 mL/min) : Onset in 222.69°C, Peak in 224.89°C e Onset in 227.22°C. (Figure 5)

IR (KBr, cnf¹) = 3584, broadband with center in 3379, 3262, 3067, 2997, 2930, 2849, 2629, 2532, 2401, 1688, 1643, 1597, 1499, 1448, 1362, 1312, 1263, 1219, 1119, 1036, 947, 860, 800, 754, 700, 602, 563. (Figure 6)

RMN^H (500 MHz, CDC1₃, TMS , t.a, rotamers, ppm) δ: 12.13 (si, 1H) ; 7.72 (m, 0.2H) ; 7.65 ( ap . t , J = 3.63 Hz, 1.8H) ; 7.44 (m, 3H) ; 7.16 (s, 0.1H) ; 7.11 (s, 0.9H) ; 6.89 (s, 0.1H) ; 6.85 (s, 0.9H) ; 6.20 (si, 0.6H) ; 4.25-4.15 (m, 2H) ; 3.98 e 3.96 (2s, 3H) ; 3.91 and 3.89 (2s, 3H) ; 3.49 (dd, J = 24.9 Hz and 11.4 Hz, 2H) ; 3.28 (dd, J = 17.1 Hz and 7.8 Hz, 1H) ; 3.12-2.96 (m, 0.2H) ; 2.80-2.59 (m, 3.8H) ; 2.35-2.16 (2sl, 1.4H) ; 2.16-2.00 (m, 3H) ; 1.94 (m, 1H) ; 1.89-1.77 (m, 2H) ; 1.56-1.41 (m, 1H) .

RMN-¹³C (125 MHz, CDC1₃, TMS , rotamers, r . t . , ppm) δ: 206.8; 155.7; 149.5; 148.6; 131.5; 131.0; 130.0; 129.3; 129.1; 128.8; 128.1; 107.3; 104.3; 60.8; 56.2; 56.0; 52.4; 52.2; 48.2; 48.0; 45.1; 44.2; 38.0; 34.4; 33.9; 32.5; 32.2; 29.3; 28.5; 26.7; 24.6.

HRMS (TOF MS ES+) = Calculated for [C24H29NO3 + H]⁺ = 380.22202; found = 380.2077. Example 9

Synthesis of donezepil hydrochloride monohydrated Form I in industrial scale.

In a 50 mL reactor, with mechanic stirring, heating system with temperature control and reflux condenser, were dissolved 10 Kg of anhydrous donepezil hydrochloride Form III of formula (IV) in a mixture of 38.4 L of methanol and 1.6 L of process water at a temperature of 50-55°C. Once the dissolution was obtained, the heating was turned off and the solution was cooled to 25±5°C. The solution was slowly transferred by cuno filter and under strong stirring to a 500 L reactor containing 200 L of ethyl tert-butyl ether cooled to 5-10°C, being careful to keep temperature within the indicated range. The mixture was stirred for 30 minutes at a temperature of 5-10°C. The solid was centrifuged and was washed with 12 L of ethyl tert-butyl ether. Then, the solid was dried in an air recirculating oven at 35±5°C. 9.619 Kg (92.2%) of donepezil hydrochloride monohydrated Form I de formula (V) were obtained, in the form of a white crystalline solid with 99.95% of HPLC purity, 0.03% of individual impurity, 5.2% of humidity determined by KF and a solvent residual of 1.717 ppm of etil- terc-butil eter, 0 ppm of methanol and 0 ppm of ethyl acetate.

Claims

1- Process for preparing donepezil hydrochloride monohydrated Form I, represented by formula (V) :

comprising the following steps:

(a) Concomitant reactions of reduction of the double bond exocyclic a, β-unsaturated carbonyl and debenzylation of l-benzyl-4- [ ( 5, 6-dimethoxy- l-indanone-2-ylidene ) methyl] piperidine represented by formula (II) :

in the presence of 10% palladium on carbon metal catalyst and a hydrogen transfer agent, in an organic solvent or mixture of an organic solvent with water at a temperature of 53-63°C; followed by treating the reaction medium with concentrated hydrochloric acid to give the intermediate 5, 6- dimethoxy-2- [ (piperidin-4-yl ) methyl ] indan-l-one hydrochloride re resented by formula (III) ;

where X represents a leaving group selected from the group consisting of chloride, bromide, iodide, mesylate and tosylate; in the presence of a base and a phase transfer catalyst in a heterogeneous mixture of solvents consisting of water and dialkyl ether in the ratio of 1:1 to 1:10, at a temperature from 30 °C to 80°C, obtaining free base donepezil, which is dissolved in ethyl acetate or isopropyl followed by treating of solution with concentrated hydrochloric acid to obtain the Donepezil hydrochloride Form III, represented by formula (IV) :

(c) Conversion of anhydrous donepezil hydrochloride Form III in donepezil hydrochloride monohydrate Form I, by dissolving donepezil hydrochloride in methanol containing 3-6 parts of 2% to 20% water, at a temperature between 40°C and 65°C, followed by cooling of the hydroalcoholic solution at room temperature, and slow addition of the solution under stirring at 15-25 parts ethyl tert-butyl ether antisolvent, at a temperature from 0°C to 12°C. 2- Process according to claim 1, wherein the 10% palladium on carbon metal catalyst is used in an amount of 1.0 mol% to 3.0 mol%; preferably from 1.6 mol% to 2.3 mol%; more preferably from 1.8 mol% to 2.0 mol% .

3- Process according to claim 1, wherein the hydrogen transfer agent is selected from the group consisting of formic acid, ammonium formate, ammonium hypophosphite and hydrazine.

4- Process according to claim 3, wherein the hydrogen transfer agent is formic acid.

5- Process according to claim 1, wherein the hydrogen transfer agent is used in an amount of 2.5 to 12.0 equivalents; preferably of 3.0 to 5.0 equivalents; more preferably of 3.0 to 3.5 equivalents.

6- Process according to claim 1, wherein the organic solvent in step (a) is selected of the group consisting of a short hydrocarbon chain alcohol, an ether, an ester, an amide, a halogenated hydrocarbon, a hydrocarbon, an organic acid and mixture thereof.

7- Process according to claim 6, wherein the organic solvent is methanol, ethanol or isopropanol.

8- Process according to claim 7, wherein the organic solvent is isopropanol.

9- Process according to claim 1, wherein the reaction in step (a) is performed at a temperature of 56-60°C.

10- Process according to claim 1, wherein the benzyl derivative is used in an amount of 0.95 to 1.25 equivalents; preferably of 0.98 to 1.10 equivalents; more preferably of 1.00 to 1.06 equivalents.

11- Process according to claim 1, wherein the base in step (b) is selected of the group consisting of a tertiary amine, an alkali metal bicarbonate, an alkali metal carbonate and mixtures thereof. 12 - Process according to claim 11, wherein the tertiary amine is selected of the group consisting of triethylamine, diisopropylethylamine, N- methylmorpholine, N-methylpiperidine, N,N- dimethylbenzylamine, pyridine, 2-methylpyridine, 3- methylpyridine, 4-methylpyridine, 2, 4-lutidine, 2,6- lutidine, and triethanolamine .

13- Process according to claim 11, wherein the alkali metal bicarbonate is sodium bicarbonate or potassium bicarbonate.

14 - Process according to claim 11, wherein the alkali metal bicarbonate is selected from the group consisting of lithium carbonate, sodium carbonate and potassium carbonate.

15 - Process according to claim 14, wherein the alkali metal carbonate is potassium bicarbonate.

16- Process according to claim 1 or 11, wherein the base is used in an amount from 200 mol% to 600 mol%; preferably from 200 mol% to 300 mol%; more preferably from 200 mol% to 250 mol%.

17 - Process according to claim 1, wherein the phase transfer catalyst is selected from the group consisting of a quaternary ammonium salt, a quaternary phosphonium salt, a crown ether and a polyether.

18 - Process according to claim 17, wherein the phase transfer catalyst is an iodide, bromide, chloride or hydrogen sulphate of tetramethylammonium, tetraethylammonium, tetrapropylammonium, tetrabutylammonium, tetrapentylammonium, tetrahexylammonium, tetraheptylammonium, tetraoctylammonium, tetrahexyldecylammonium,

tetraoctyldecylammonium, tetradecyltrimethylammonium, hexadecyltrimethylammonium,

octadecyltrimethilammonium, tert- butyletyldimethilammonium, benzyltrimethylammonium, 1- methylpyridinium, 1-hexadecylpyridinium and 1,4- diethylpyridinium.

19- Process according to claim 18, wherein the phase transfer catalyst is tetrabutylammonium bromide.

20- Process according to claim 1 or 17, wherein the phase transfer catalyst is used in an amount ranging from 1 mol% to 25 mol%; preferably from 2.5 mol% to 10 mol%; more preferably from 4 mol% to 6 mol%.

21- Process according to claim 1, wherein the dialkyl ether in step (b) is selected from the group consisting of methyl- tert-butyl ether, ethyl- tert- butyl ether, dibutyl ether and mixtures thereof.

22- Process according to claim 21, wherein the dialkyl ether is ethyl- tert-butyl ether.

23- Process according to claim 1, wherein the ratio of water and dialkyl ether in the mixture of solvents in step (b) is from 1.0:1.0 to 1.0:3.0, preferably from 1.0:1.0 to 1.0:1.3.

24- Process according to claim 1, wherein the benzylation reaction in step (b) is performed at a temperature from 45°C to 65°C, preferably from 50°C to 60°C.

25- Process according to claim 1, wherein donepezil hydrochloride dissolution in step (c) is performed in 4-5 parts of methanol having from 3.5% to 5.5% of water, at a temperature between 50°C and 55°C, cooling the hydroalcoholic solution at room temperature, and slow addition of the solution under stirring at 15-25 parts of ethyl tert-butyl ether antisolvent at a temperature from 5°C to 10°C.

26- Process for preparing donepezil hydrochloride Form III represented by formula (IV) :

comprising the steps (a) and (b) according to claim 1. 27- Process for preparing 5, 6-dimethoxy-2- [ (piperidin-4- yl) methyl] indan-l-one hydrochloride, represented by formula III:

comprising the step (a) according to claim