IMPROVED PROCESS FOR THE PREPARATION OF (l-BENZYL.4-(5,6,-DIMETHOXYINDANONE-2YL)METHYLPIPERIDINE) HYDROCHLORIDE-FORM III
Technical field of invention
The present invention is directed to an improved industrially viable, cost effective process for manufacturing pure racemic crystalline anhydrous form of (1 -benzyl-4-(5,6,-
*
dimethoxyindanone-2yl)methylpiperidine) hydrochloride Form III commonly known as Donepezil hydrochloride with a purity level of greater than 99.9%.
Background of invention
Donepezil hydrochloride (1 -benzyl-4-(5,6,-dimethoxyindanone-2yl)methylpiperidine) hydrochloride of formula-I

belongs to a group of selective acetylcholine esterase inhibitor used for the treatment of mild to moderate Alzheimer's disease. Donepezil hydrochloride is a white crystalline powder. It is freely soluble in chloroform, water and glacial acetic acid, slightly soluble in ethanol and acetonitrile and insoluble in ethyl acetate and n-hexane.
US5985864 discloses polymorphic form II, IV and V of donepezil hydrochloride and process of preparation thereof which comprises recrystallising donepezil hydrochloride in suitable solvent or desired form can also be obtained by dissolving donepezil hydrochloride in suitable solvent and precipitating the desire form by addition of an antisolvent alternatively donepezil free base is dissolved in suitable solvent and treated with hydrochloric acid or hydrogen chloride or by humidification of any form to give desired form.
US6140321 discloses polymorphic form III of donepezil hydrochloride and process for preparation thereof which process comprises recrystallizing donepezil hydrochloride Form I or by dissolving donepezil hydrochloride form II in suitable solvent and precipitating the desire form by addition of an antisolvent alternatively donepezil free base is dissolved in suitable solvent and

treated with hydrochloric acid or hydrogen chloride or by humidification of any form to give desired form III.
US2004229914 discloses polymorphic form VI of donepezil hydrochloride and process for preparation thereof which process comprises dissolving donepezil free base obtained form patent 1847/CHE/2007 under process at the patent office in suitable alcoholic solvent at 60-65°C and treated with hydrochloric acid or hydrogen chloride at 25-30°C to form crystalline form VI which is further treated with etheral solvent at 25-30°C for 5-10 hr s to give Form VI.
WO2002026709 discloses polymorphic form III of donepezil HCl by dissolving donepezil in ethanol and adding hydrochloric acid to get the desired form.
WO2004092137 discloses polymorphic form crystalline form HI, H2 monohydrate and amorphous form there of.
Its apparent from most of the prior art that, the preparation of donepezil has certain disadvantages such as the use of hazardous raw materials like lithium diisopropyl amine and n-butyllithium, costly raw materials like platinum oxide, imviable reaction conditions like temperature below -SO°C and low yields i.e. 62%. Therefore, there is a continuing need for developing a new process for the manufacturing of racemic donepezil and salt thereof which is cost effective and industrially viable.
Summary of the invention
The present invention describes an industrially viable process for manufacturing substantially pure racemic mixture of (1 -benzyl-4-(5,6,-dimethoxyindanone-2yl)methylpiperidine)hydrochloride Form III from donepezil free base form D, with a purity level of greater than 99.9%.
The process comprises of reacting 5,6-dimethoxy-l-indanone with l-benzyl-4-piperidine carboxaldehyde followed by reduction to give solid crystalline Form D of Donepezil which is further converted to racemic crystalline form of Donepezil hydrochloride form I (Scheme VII).


Another aspect of the present invention is to provide a racemic, crystalline, substantially pure form of donepezil hydrochloride form III with a HPLC purity level of greater than 99.9% with impurity level of less than 0.1%.
Description of the figures
FIGURE I: XRPD of substantially pure form of crystalline Donepezil hydrochloride Form III FIGURE II: DSC of substantially pure form of crystalline Donepezil hydrochloride Form in
Detailed description of the invention
The present invention provides an improved process for the preparation of l-Benzyl-4-(5, 6 dimethoxy-l-indanone)-2-yl) methyl piperidine hydrochloride Form III, which comprises of following steps:
a) Condensation of 5, 6-dimethoxy-l-indanone with l-benzyl-4-piperidine carboxaldehyde
using a base selected from a group consisting of metal hydroxide like sodium hydroxide,
potassium hydroxide; metal carbonates like potassium carbonate, sodium bicarbonate or
metal alkoxide like sodium methoxide, sodium ethoxide, potassium sec-butoxide or
potassium ter. butoxide
b) addition of water after reaction completion followed by neutralization with suitable acid
c) separation of the orgamc layer and treatment with activated carbon

acidification of the organic layer with isopropanolic hydrogen chloride and removal of solvent by distillation
dissolving the residue in a suitable alcoholic solvent and addition of suitable ketonic solvent to precipitate crystalline solid form of l-Benzyl-4-(5, 6 dimethoxy-l-indanone)-2-ylidinyl) methyl piperidine hydrochloride
reduction of die compound obtained from the step e above with suitable metal catalyst under pressure below 3kg/cm in a suitable organic solvent/s, filtration of the reaction completion and removal of the solvent by distillation
dissolving the residue in a suitable halogenated organic solvent followed by neutralization with a suitable base, separation of the organic layer and treatment with activated carbon acidification of the organic layer with isopropanolic hydrogen chloride and removal of solvent by distillation
dissolving the residue in a suitable alcoholic solvent and suitable ketonic organic solvent to precipitate crude donepezil hydrochloride
dissolving donepezil hydrochloride, obtained form above in a mixture of purified water and an organic solvent, adjusting the pH to basic with a suitable base, isolation of compound, washing with water and drying to obtain racemic l-Benzyl-4-(5, 6 dimethoxy-1-indanone)-2-yl) methyl piperidine, donepezil form D
dissolving crystalline donepezil form D obtained from the stepj above in a suitable organic solvent and treatment with activated carbon
acidification of the organic layer with isopropanolic hydrogen chloride and removal of solvent by distillation followed by swapping with a suitable alcoholic solvent. I isolating racemic l-Benzyl-4-(5, 6 dimethoxy-l-indanone)-2-yl) methyl piperidine hydrochloride (Donepezil hydrochloride Form III) by addition of suitable ketonic solvent in the solvent layer obtained form the step I above.
dissolving donepezil form D obtained as per the procedure given in 1847/CHE/2007 in a suitable organic solvent and treatment with activated carbon

b. acidification of the organic layer with isopropanolic hydrogen chloride and removal of
solvent by distillation followed by swapping with a suitable alcoholic solvent.
c. isolating racemic 1 -Benzyl-4-(5, 6 dimethoxy-1 -indanone)-2-yl) methyl piperidine
hydrochloride (Donepezil hydrochloride form III) by addition of suitable ketonic solvent in
the solvent layer obtained form the step b above.
*
The base used for condensation was dissolved in a suitable alcoholic solvent such as methanol, ethanol or isopropanol; most preferably methanol.
The condensation is carried out in organic solvent, selected from a group of halogenated organic solvent such as methylene chloride, ethylene chloride or chloroform; most preferably methylene chloride.
The neutralization of the reaction mixture as in step b is carried using hydrochloric acid.
The alcoholic solvent used in the step e is selected from methanol, ethanol and isopropanol; most preferably methanol.
The ketonic organic solvent used is selected from acetone, methyl ethyl ketone; most preferably acetone.
The reduction of 1 -benzyl-4(5,6-dimethoxy-1 -indanone)-2-ylidene methyl piperidine hydrochloride is carried out in the presence of Raney nickel or palladium on carbon in an organic solvent or mixture thereof at different ratios in suitable solvent selected from ethanol, methanol and isopropanol, acetic acid or mixture thereof; most preferably mixture at acetic acid and methanol at various ratios
The organic solvent used for reduction is selected from methanol, ethanol, isopropanol or acetic acid or mixture thereof, most preferably mixture of acetic acid with methanol in 1:1 ratio.
The reduction is carried under pressure below 3kg/cm ; most preferably 1.5 to 2kg/cm . The neutralization of the reduced compound as in step g, is carried out in the presence of suitable base selected from sodium bicarbonate, potassium bicarbonate and like.
The basification of the compound as in step j is carried out in the presence of suitable aqueous base selected from sodium hydroxide, potassium hydroxide and like.
The organic solvent used in step k is selected from a group consisting of halogenated organic solvent such as methylene chloride, ethylene chloride or chloroform most preferably methylene chloride.

The alcoholic solvents used in the stepj is selected from methanol, ethanol and isopropanol; most preferably methanol.
The ketonic organic solvent used is selected from acetone, methyl ethyl ketone, most preferably acetone.
The examples are provided to illustrate particular aspects of the disclosxure and do not limit the scope of the present invention as defined by the claims.
Example
Step 1: Preparation of l-Benzyl-4-(5, 6 Dimethoxy-l'indanone)-2-ylidinyl) methyl piperidine hydrochloride.
To 5,6-dimethoxy-l- indanone (lOOg) in methylene chloride (1000ml) was added 1-benzyl piperidine-4-carboxaldehyde (150.0 g) and the reaction mixture was stirred for 15 minutes at 25-30°C for dissolution. The reaction mixture was cooled to 0-5°C and to it was added potassium hydroxide dissolved in methanol solution (48.0 g in 200 ml methanol) in a period of 30-60 minutes and stirred for 30 minutes at 0-5°C. The temperature of the reaction mass was raised to 25-30°C and the stirring continued for 2 hours. The reaction was monitored by thin layer chromatography for absence of 5, 6-dimethoxy-l-indanone. After the completion of the reaction piuified water (300mL) was added and the mixture was stirred for 15 minutes. The pH of the reaction mass was adjusted to 6.5-7.5 with concentrated hydrochloric acid at 25-30°C and stirred for 30 minutes. The layers were separated and the organic layer was extracted with methylene chloride. The methylene chloride layer was washed with purified water, treated with activated carbon (5g) and filtered. The pH of the filtrate was acidified to <2.0 with isopropanolic hydrochloride. The organic layer was distilled under vacuiun, methanol (200.OmL) was added to the residue and stirred for 15 minutes followed by the addition of acetone (lOOOmL) and the stirring was continued for 3 hours at 25-30°C . The compound was filtered and washed with acetone, to the wet cake was added methanol (200.0mL) and the mixture was stirred for 15 minutes followed by the addition of acetone (600.0mL) and stirring was continued for 3 hours. The mixture was filtered, washed with acetone (200.0mL) and dried at 60-65°C to obtain the title compound. : 195.g)(% Yield: 913%) Step 2: Preparation of racemic mixture of substantially pure crystalline solid form of Donepezil

l-Benzyl-4-(5, 6 Dimethoxy-l-indanone)"2-ylidinyl) methyl piperidine hydrochloride (50.0g) obtained form the step 1 above was taken in a mixture of acetic acid (650.0ml) and methanol (650.0 ml) and stirred at 25-30°C for 15 minutes. The reaction content was heated to 40-45°C for complete dissolution cooled to 25-30°C and to it was added 5% Pd-C(50% wet) (2.5g) and was hydrogenated under 1.5-2.0 Kg/cm pressure. The reaction mixture was filtered and the solvent was distilled under vacuum below 60°C , cooled to 25-30°C. The residue was taken in methylene chloride (500mL) and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution (50g NaiCOa in 500 mL of purified water), the organic layer was separated and the aqueous layer was extracted with methylene chloride, both the methylene chloride layers were combined, washed with water, treated with activated carbon(5.0g) and filtered. The pH of the filtrate was acidified to <2.0 with isopropanolic hydrochloride at 25-30°C. The solvent was distilled under vacuum below 40°C and cooled to 25-30°C, methanol (550mL) was added to the residue, stirred for 10 minutes followed by the addition of acetone (250mL) and the stirring was continued for 3 hours at 25-30'°C , the compound was filtered and washed with acetone. To the wet compound was added purified water (80mL) and methanol (240niL) and content was stirred at 25-30°C for 15 minutes for complete dissolution. The pH is adjusted to 12.5-13 with 20% sodium hydroxide solution (20.0mL) and stirred for 5 minutes at 25-30°C followed by further addition of purified water (600mL) and the stirring was continued for 2 hrs at 25-30°C. The compound was filtered, washed with purified water (50mL) and dried for 30 minutes to yield crystalline racemic donepezil free base. (Dry weight: 37g, HPLC: 99.5 % % Yield: 80%)
Step 3: Preparation of racemic mixture of substantially pure crystalline solid of Donepezil Hydrochloride Form III
Donepezil(35g) free base obtained from the step 2 above was taken in methylene chloride (350mL) and stirred for complete dissolution and was treated with activated carbon(1.75g) and filtered, the pH of the filtrate was adjusted to <2.0 with isopropanolic hydrochloride at 25-30°C and the organic layer was distilled and swapped with methanol (175mL). The residue was dissolved in methanol (350mL) and to it was added acetone (700ml) to crystallize Form III of Donepezil hydrochloride, the crystals were filtered and washed with acetone (70mL) and dried to get hydrochloride salt of Donepezil Form III. (Dry weight: 32g, HPLC: 99.9 % % Yield: 85%)

We claim
1. An improved process for industrial manufacture of l-Ben2yl-4-(5, 6 dimethoxy-l-indanone)"2-ylidinyl) methyl piperidine i.e. hydrochloride form III comprising:
a. Condensation of 5,6-dimethoxy-l-indanone with l-benzyl-4-piperidine carboxaldehyde
using a base selected from a group consisting of metal hydroxide like sodium hydroxide,
potassium hydroxide; metal carbonates like potassium carbonate, sodium bicarbonate
or metal alkoxide like sodium methoxide, sodium ethoxide, potassium sec-butoxide or
potassium ter. butoxide dissolves in methanol, ethanol or isopropanol carried out in
halogenated organic solvent selected from group comprising of methylene chloride,
ethylene chloride or chloroform most preferably methylene chloride
b. addition of water after reaction completion followed by neutralization with suitable acid,
most preferably using hydrochloric acid
c. separation of the organic layer and treatment with activated carbon
d. acidification of the organic layer with isopropanolic hydrogen chloride and removal of
solvent by distillation
e. dissolving the residue in a suitable alcoholic solvent selected from a group comprising
of methanol, ethanol and isopropanol and addition of suitable ketonic solvent to
precipitate crystalline solid form of l-Benzyl-4-(5, 6 dimethoxy-l-indanone)-2-ylidinyl)
methyl piperidine hydrochloride
f. reduction of the compound obtained from the step e above with suitable metal catalyst
under pressure below 3kg/cm2 in a suitable organic solvent/s, filtration of the reaction
completion and removal of the solvent by distillation
g. dissolving the residue in a suitable halogenated solvent selected from a group
comprising of methylene chloride, ethylene chloride or chloroform most preferably
methylene chloride, followed by neutralization with a suitable base selected from group
comprising of sodium hydroxide, potassium hydroxide, sodium bicarbonate and
potassium bicarbonate and separation of the organic layer and treatment with activated
carbon
h. acidification of the organic layer with isopropanolic hydrogen chloride and removal of solvent by distillation

i. dissolving the residue in a suitable alcoholic solvent elected from a group comprising of
methanol, ethanol and isopropanol and suitable ketonic organic solvent to precipitate the
solid j. dissolving the compoimd obtained form the step i above in a mixture of purified water
and an organic solvent, adjusting the pH to basic with a suitable base, isolation of
compound, washing with water and drying to obtain racemic l-Benzyl-4-(5, 6
dimethoxy-l-indanone)-2-yl) methyl piperidine(donepezil free base) in a substantially
pure form, k, dissolving donepezil free base in a suitable organic solvent and treatment with activated
carbon 1. acidification of the organic layer with isopropanolic hydrogen chloride and removal of
solvent by distillation followed by swapping with a suitable alcoholic solvent m. Isolating racemic l-Benzyl-4-(5, 6 dimethoxy-l-indanone)-2-yl) methyl piperidine
hydrochloride (Donepezil hydrochloride) by addition of suitable ketonic solvent in the
solvent layer obtained form the step I above. 2. An improved process for industrial manufacture of l-Benzyl-4-(5,6 dimethoxy-l-indanone)-2-ylidinyl) methyl piperidine i.e. hydrochloride form III comprising:
a. dissolving donepezil form D obtained as per the procedure given in 1847/CHE/2007 in a
suitable organic solvent and treatment with activated carbon
b. acidification of the organic layer with isopropanolic hydrogen chloride and removal of
solvent by distillation followed by swapping with a suitable alcoholic solvent.
c. isolating racemic l-Benzyl-4-(5, 6 dimethoxy-l-indanone)-2-yl) methyl piperidine
hydrochloride (Donepezil hydrochloride) by addition of suitable ketonic solvent in the solvent
layer obtained form the step b above.
i. The process for industrial manufacture of l"Benzyl-4-(5, 6 dimethoxy-l-indanone)-2-ylidinyl) methyl piperidine according to claim 1 and 2, wherein the reduction of l-benzyl-4(5,6-dimethoxy-l-indanone)-2-ylidene methyl piperidine hydrochloride is carried out in the presence of Raney nickel or palladium on carbon in an organic solvent selected from a group comprising of ethanol, methanol and isopropanol, acetic acid or mixture thereof; most preferably mixture at acetic acid and methanol at various ratios most preferably methanol: acetic acid in 1:1 ratio

4. The process for industrial manufacture of l-Benzyl-4-(5, 6 dimethoxy-l-indanone)-2-ylidinyl) methyl piperidine according to claim 1 and 2, wherein the reduction is carried out under pressure below 3Kg/cm2, preferably between 1.5 to 2 Kg/cm2.
5. The process for industrial manufacture of l-Benzy1-4-(5, 6 dimethoxy-l-indanone)-2-ylidinyl) methyl piperidine according to claim 1 and 2, wherein the solvent used for dissolving donepezil is selected from a group comprising of halogenated organic solvent such as methylene chloride, ethylene chloride or chloroform most preferably methylene chloride.
6. The process for industrial manufacture of l-Benzyl-4-(5, 6 dimethoxy-l-indanone)-2-ylidinyl)
methyl piperidine according to claim 1 and 2, wherein solvent used for swapping is solvent
selected from a group comprising of ethanol, methanol and isopropanol most preferably
methanol.
7. The process for industrial manufacture of l-Benzyl-4-(5, 6 dimethoxy-l-indanone)-2-ylidinyl) methyl piperidine according to claim 1 and 2, wherein ketonic solvent used is selected from acetone, methyl ethyl ketone, most preferably acetone.
8. Substantially pure anhydrous crystalline racemic form III of l-Benzyl-4-(5, 6 dimethoxy-1-indanone)-2-ylidinyl) methyl piperidine hydrochloride with a purity level of greater than 99.9%.