Field of the invention
The present invention relates to a process for the preparation of l-benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine and acid addition salts thereof. Particularly, the present invention relates to a process for the preparation of l-benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine hydrochloride.
Background and prior art
Donepezil hydrochloride is chemically known as l-benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine hydrochloride of Formula-I. It is useful in the treatment of Dementia and Alzheimer's disease.

Formula-I The preparation of donepezil hydrochloride was first described in US 4,895,841. The process disclosed by this patent involves conversion of l-benzyl-4-piperidinone to 1-benzyl-4-piperidine carboxaldehyde in the presence of n-butyllithium, which on further reaction with 5,6-dimethoxy-l-indanone in the presence of a strong base such as lithium diisopropylamide (LDA) under inert atmosphere followed by reduction of the obtained compound gives the compound of Formula-I with an overall yield of 50.8%. The disadvantage of this process is the use of hazardous reagents such as n-butyl lithium and LDA. The process steps are depicted in the following reaction scheme 1.Scheme 1:


US 5606064 discloses a process for the preparation of donepezil, which involves the reaction between 5,6-dimethoxy indanone and pyridine-4-carboxaldehyde to yield 5,6-dimethoxy-2-pyridin-4-yl-methylene-indan-l-one, which upon condensation with benzyl bromide followed by reduction of the obtained compound with platinum oxide to afford the compound of Formula-I with an overall yield of 58.5%. The disadvantage of this process is using costly catalyst such as platinum oxide.
WO 97/22584 discloses a process for the preparation of donepezil hydrochloride, which involves a multi-step process starting from pyridine-4-aldehyde to obtain donepezil hydrochloride. The disadvantage of this process is it involves multiple steps wherein an overall yield of 19.3% of donepezil hydrochloride is obtained.
US 2007/0117846 discloses a process for the preparation of donepezil, which involves the catalytic hydrogenation of l-benzyl-4-[(5,6-dimethoxy-l-indanon)-2-ylidene]methylpiperidine using Raney nickel catalyst in a suitable solvent such as water, an alcohol, acetic acid, an acetic acid ester, an ether, benzene, hexane, toluene, tetrahydrofuran, dioxane or a mixed solvent thereof. In this process Donepezil hydrochloride is obtained in 75-80% yield.
WO 2007/015052 discloses a process for the preparation of donepezil according to the following Scheme 2.

Scheme 2

where P is methyl
This process involves three steps to prepare donepezil. The first step is the condensation of 5,6-dimethoxy-l-indanone and isonicotinic acid methyl ester in the presence of alkali metal alkoxides, preferably sodium methoxide and aromatic solvent such as toluene. The second step is benzylation with benzyl halide. The third step is reduction with a hydride or hydrogenation in the presence of noble metals such as Pt, Ni, Pd or its oxide as a catalyst. The disadvantage of this process is the use of costly materials such as platinum oxide.
US 6252081 discloses a process, which involves the selective reduction of pyridinium ring of l-benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methylpyridinium salt using platinum oxide as catalyst and methanol as a solvent. This process also leads to the formation of impurities, which are difficult to separate and affects the overall reaction yield and the purity of Donepezil hydrochloride of Formula-I. The process steps are depicted in the following reaction Scheme 3.

Scheme 3

US 20040143121 discloses a process for the preparation of donepezil which comprises the reduction of compound 4-[(5,6-dimethoxy-l-indanon)-2-ylidene]methylpyridine using platinum dioxide or Pd/C as catalyst and in a mixture of solvents such as acetic acid and methanol. The disadvantage of this process is use of costly raw material like platinum dioxide.
US 6649765 teaches a process for the preparation of l-benzyl-4-[(5,6-dimethoxy-l-indanon)-2-yl]methylpiperidine hydrochloride which comprises hydrogenating (5,6-dimethoxy-2-(pyridine-4-yl)methylene inda-1-one with a noble metal oxide catalyst in an organic solvent at 20-50°C and 10-45 psi gauge pressure to obtain 4-[(5,6-dimethoxy-l-indanon)-2-yl]methylpiperidine, alkylating said 4-[(5,6-dimethoxy-l-indanon)-2-yl]methylpiperidine with an alkylating agent in an organic solvent at 20-80°C followed by addition of methanolic-HCl to obtain l-benzyl-4-[(5,6-dimethoxy-l-indanon)-2-yl]methylpiperidine hydrochloride in 95.5% over all yield.
The prior art processes use hazardous reagents and costly raw materials and therefore, there is a need to develop simple processes for preparing donepezil.
Summary of the invention
The present invention provides a process for the preparation of donepezil, 1-benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine, of Formula-II,


Form ula-ll said process comprising: obtaining a reaction mixture of l-benzyl-4-[(5,6-dimethoxy-l-indanon)-2-ylidene]methylpiperidine of Formula-Ill and an alcoholic solvent;

hydrogenating said reaction mixture with a catalyst in presence of an organic acid at a hydrogen gas pressure to obtain crude l-benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine of Formula-II; dissolving the crude l-benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine of Formula II in water and basifying with a base to obtain a resulting solution; and extracting said resulting solution with an organic solvent to obtain substantially pure 1-benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine of Formula II.
The present invention also provides a process for the preparation of acid addition salts of donepezil by reacting l-benzyI-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine of Formula II with an acid to obtain a corresponding acid addition salt of donepezil of Formula-IV in a lower alcohol.
The present invention particularly provides a process for the preparation of donepezil hydrochloride, l-benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine hydrochloride of Formu!a-I.
These and other features, aspects, and advantages of the present subject matter will become better understood with reference to the following description and appended claims. This Summary is provided to introduce a selection of concepts in a simplified form. This Summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used to limit the scope of the claimed subject matter.

Detailed description of the invention
Accordingly, the present invention provides a process for the preparation of donepezil, l-benzyI-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine, of Formula-II,

Form ula-ll
said process comprising:
a) obtaining a reaction mixture of l-benzyl-4-[(5,6-dimethoxy-l-indanon)-2-
ylidene]methylpiperidine of Formula-Ill and an alcoholic solvent;

b) hydrogenating said reaction mixture with a catalyst in presence of an organic acid at a hydrogen gas pressure to obtain crude l-benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine of Formula-II;
c) dissolving the crude l-benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine of Formula II in water and basifying with a base to obtain a resulting solution; and
d) extracting said resulting solution with an organic solvent to obtain substantially pure 1-benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine of Formula II.
The compound of Formula-II of the present invention may exist in the form of its acid-addition salt that retains the biological effectiveness and properties of the compound of Formula-II and is formed from suitable acids. The acid-addition salts include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, sulphamic acid, phosphoric acid, nitric acid, oxalic acid, maleic acid, benzenesulphonic acid, p-toluenesulphonic acid,

methanesulphonic acid, ethanesulphonic acid and the like. The chemical modification of a pharmaceutical compound into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds.
The present invention also provides a process for the preparation of acid addition salts of donepezil of Formula-IV,

said process comprising:
a) obtaining a reaction mixture of l-benzyl-4-[(5,6-dimethoxy-l-indanon)-2-
ylidene]methylpiperidine of Formula-Ill and an alcoholic solvent;

b) hydrogenating said reaction mixture with a catalyst in presence of an organic
acid at a hydrogen gas pressure to obtain crude 1-benzyl-4-[(5, 6-dimethoxy-l-
indanon)-2-yl] methylpiperidine of Formula-II;


Formula-ll
c) dissolving said crude l-benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine of Formula II in water and basifying with a base to obtain a resulting solution;
d) extracting said resulting solution with an organic solvent to obtain substantially pure l-benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine of Formula II; and
e) reacting said 1-benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine of Formula-II with an acid to obtain corresponding acid addition salt of donepezil of Formula-IV in a lower alcohol.
An embodiment of the present invention provides a process for the preparation of donepezil and acid addition salts thereof, wherein the reaction mixture of l-benzyl-4-[(5,6-dimethoxy-l-indanon)-2-ylidene]methylpiperidine of Formula-Ill is prepared in an alcoholic solvent. When the above mentioned alcoholic solvent is specifically illustrated, "alcoholic solvent" means, for example methanol, ethanol, isopropanol, or the like, preferably methanol.
It is an embodiment of the present invention to provide a process for the preparation of donepezil and acid addition salts thereof, wherein the catalyst for hydrogenation is either palladium or Raney nickel and preferably Raney nickel.
Another embodiment of the present invention is to provide a process for the preparation of donepezil and acid addition salts thereof, wherein the organic acid is an aliphatic sulphonic acid, an aryl sulphonic acid or a mixture thereof. The organic acid increases the reaction rate and thus donepezil is obtained in good yield with high purity in short duration.

The aliphatic or aryl sulphonic acid used in the present invention is selected from the group consisting of methanesulphonic acid, ethanesulphonic acid, p-toluenesulphonic acid, trifluoromethanesulphonic acid and camphor sulphonic acid.
It is also an embodiment of the present invention to provide a process for the preparation of donepezil and acid addition salts thereof, wherein the organic acid is methanesulphonic acid.
Yet another embodiment of the present invention is a process for the preparation of donepezil and acid addition salts thereof, wherein the hydrogen gas pressure is 4 to 5 Kg/cm2, preferably 5 Kg/cm2. The hydrogenation is carried out at room temperature.
An embodiment of the present invention provides a process for the preparation of donepezil and acid addition salts thereof, wherein organic solvent is ethyl acetate or dichloromethane.
Another embodiment of the present invention provides a process for the preparation of donepezil and acid addition salts thereof, wherein the base is selected from the group consisting of alkali or alkaline earth metal hydroxides, alkali metal alcoholates, alkali metal carbonates, and amines.
Suitable bases are alkali metal hydroxides such as, for example, sodium hydroxide, potassium hydroxide, alkaline earth metal hydroxides such as, for example, calcium hydroxide, alkali metal alcoholates such as, for example, sodium methylate, potassium methylate, sodium ethylate and potassium ethylate, alkali metal carbonates such as, for example, sodium carbonate and potassium carbonate, and amines such as, for example, ammonia, and triethylamine.
Further, an embodiment of the present invention also includes a process for the preparation of donepezil and acid addition salts thereof, wherein the lower alcohol is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, n-pentanol, n-hexanol, or mixtures thereof and preferably isopropanol.
The process steps for the preparation of l-benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine of Formula-II and acid addition salts thereof are depicted in the following Scheme 4.

Scheme 4

Process for the preparation of l-benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methyl piperidine
The present invention also provides a process for the preparation of donepezil, 1-benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine hydrochloride of Formula-II,

said process comprising:
a) obtaining a reaction mixture of l-benzyl-4-[(5,6-dimethoxy-l-indanon)-2-ylidene]methylpiperidine of Formula-Ill and methanol;


b) hydrogenating said reaction mixture with raney nickel in presence of methanesulfonic acid at a hydrogen gas pressure of 5 kg/cm2 to obtain crude 1-benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine of Formula-II;
c) dissolving said crude l-benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine of Formula-II in water and basifying with 50% sodium hydroxide to obtain a resulting solution; and
d) extracting said resulting solution with ethyl acetate to obtain substantially pure 1-benzyl-4-[(5,6-dimethoxy-l-indanon)-2-yl] methylpiperidine of Formula II.
Process for the preparation of l-benzyI-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methyl piperidine hydrochloride
The present invention also provides a process for the preparation of donepezil hydrochloride, l-benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine hydrochloride of Formula-I

said process comprising:
a) obtaining a reaction mixture of l-benzyl-4-[(5,6-dimethoxy-l-indanon)-2-ylidenejmethylpiperidine of Formula-Ill and methanol;


b) hydrogenating said reaction mixture with raney nickel in presence of methanesulfonic acid at a hydrogen gas pressure to obtain crude l-benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine of Formula-II;
c) dissolving said crude l-benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine of Formula-II in water and basifying with 50% sodium hydroxide to obtain a resulting solution;
d) extracting said resulting solution with ethyl acetate to obtain substantially pure 1-
benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine of Formula II; and
e) reacting said l-benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine of
Formula-II with hydrochloric acid to obtain l-benzyl-4-[(5, 6-dimethoxy-l-
indanon)-2-yl] methylpiperidine hydrochloride of Formula-I in isopropyl alcohol.
The process steps for the preparation of l-benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine hydrochloride of Formula-I are depicted in the following Scheme 5.
Scheme S


EXAMPLES
The process steps of the present invention are described in the following examples,
which are illustrative in nature only and should not be construed as limiting the scope of the
invention in any manner.
Example 1
Preparation of donepezil hydrochloride, l-benzyl-4-(5, 6-dimethoxy-l-indanon)-2-yI] methylpiperidine hydrochloride of Formula-I
a. Preparation of l-benzyl-4-(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine
(Donepezil)
20g of l-benzyl-4-[(5,6-dimethoxy-l-indanon)-2-ylidene]methylpiperidine is charged in an autoclave containing 850ml of methanol. 2.6g of Raney Nickel and then 8g of methanesulphonic acid are introduced into the reaction vessel. The reaction mixture is hydrogenated with stirring at a pressure of 5 kg/cm2 at room temperature for 3-4 hours.
After completion of the hydrogenation, the Raney nickel catalyst is filtered from the reaction mixture and methanol is distilled out from the filtrate. The resulting crude 1-benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine of Formula-II is dissolved in 100ml of water and basified with 50% sodium hydroxide. The resulting solution is extracted with ethyl acetate and the organic layer is concentrated to obtain 18g of donepezil (90% yield) having HPLC purity >98%.
b. Preparation of l-benzyl-4-(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine
hydrochloride
4g of donepezil is taken in a round-bottomed flask containing 30ml of isopropyl alcohol with constant stirring, followed by addition of 3.5ml HC1 in isopropyl alcohol. The reaction mixture becomes clear solution and stirring is continued for 1 hour, and the mixture gets converted to its hydrochloride. The precipitated donepezil hydrochloride is filtered out and then dried under vaccum to obtain 4g of donepezil hydrochloride (91.3%) with HPLC purity > 99.9%.
Advantages of the present invention
The previously described versions of the subject matter and its equivalent thereof have many advantages, including those which are described below:

1. The present invention provides a process for the preparation of Donepezil of Formula II having an HPLC purity >98%.
2. The present invention provides a process for the preparation of Donepezil of Formula II in >90% molar yield.
Although the subject matter has been described in considerable detail with reference to certain preferred embodiments thereof, other embodiments are possible. As such, the spirit and scope of the appended claims should not be limited to the description of the preferred embodiment contained therein.

We claim:
1. A process for the preparation of l-benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl]
methylpiperidine (donepezil), of FormuIa-II,

said process comprising:
a) obtaining a reaction mixture of l-benzyl-4-[(5,6-dimethoxy-l-indanon)-2-
ylidene]methylpiperidine of Formula III and an alcohol;

b) hydrogenating said reaction mixture with a catalyst in presence of an organic acid at a hydrogen gas pressure to obtain crude l-benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine of Formula II;
c) dissolving the crude l-benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine of Formula II in water and basifying with a base to obtain a resulting solution; and
d) extracting said resulting solution with an organic solvent to obtain substantially pure l-benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine of Formula II.
2. A process for the preparation of acid addition salts of 1 -benzyl-4-[(5, 6-dimethoxy-1 -
indanon)-2-yl] methylpiperidine (donepezil) of Formula-IV,


said process comprising:
a) obtaining a reaction mixture of l-benzyl-4-[(5,6-dimethoxy-l-indanon)-2-
ylidene]methylpiperidine of Formula-Ill and an alcohol;

b) hydrogenating said reaction mixture with a catalyst in presence of an organic
acid at a hydrogen gas pressure to obtain crude l-benzyl-4-[(5, 6-dimethoxy-l-
indanon)-2-yl] methylpiperidine of Formula-II;

Formula-ll
c) dissolving said crude l-benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl]
methylpiperidine of Formula II in water and basifying with a base to obtain a
resulting solution;

d) extracting said resulting solution with an organic solvent to obtain substantially pure l-benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine of Formula II; and
e) reacting said l-benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine of Formula-II with an acid to obtain a corresponding acid addition salt of 1-benzyl-4-[(5, 6-dimethoxy-l-indanon)-2-yl] methylpiperidine (donepezil) of Formula-IV in a lower alcohol.

3. The process as claimed in claim 1 or 2, wherein the alcohol is selected from a group consisting of methanol, ethanol and isopropanol, or mixtures thereof, preferably methanol.
4. The process as claimed in claim 1 or 2, wherein the catalyst is palladium or Raney nickel, preferably Raney nickel.
5. The process as claimed in claim 1 or 2, wherein the organic acid is either an aliphatic sulphonic acid or an aryl sulphonic acid, or mixtures thereof.
6. The process as claimed in claim 5, wherein the aliphatic sulphonic acid is methanesulphonic acid.
7. The process as claimed in claim 1 or 2, wherein the hydrogen gas pressure is in the range of 4 to 5 Kg/cm2.
8. The process as claimed in claim 1 or 2, wherein the organic solvent is ethyl acetate or dichloromethane, preferably ethyl acetate.
9. The process as claimed in claim 1 or 2, wherein the base is selected from a group consisting of alkali or alkaline earth metal hydroxide, alkali metal alcoholate, alkali metal carbonate, and amine.
10. The process as claimed in claim 9, wherein the alkali or alkaline earth metal hydroxide is selected from a group consisting of sodium hydroxide, potassium hydroxide and calcium hydroxide, preferably sodium hydroxide.
11. The process as claimed in claim 9, wherein the alkali metal alcoholate is selected from a group consisting of sodium methylate, potassium methylate, sodium ethylate and potassium ethylate; the alkali metal carbonate is sodium carbonate or potassium carbonate; and the amine is either ammonia or triethylamine.

12. The process as claimed in claim 2, wherein the acid is selected from a group
consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid,
sulphamic acid, phosphoric acid, nitric acid, oxalic acid, maleic acid,
benzenesulphonic acid, p-toluenesulphonic acid, methanesulphonic acid, and
ethanesulphonic acid.
13. The process as claimed in claim 2, wherein the acid is hydrochloric acid.
14. The process as claimed in claim 2, wherein the lower alcohol is selected from a group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, n-pentanol and n-hexanol, or mixtures thereof, preferably isopropanol.

To
The Controller of Patents,
Patent Office at Chennai