FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patent Rules, 2006
COMPLETE SPECIFICATION
(See section 10; rule 13)
1.Title of the invention: "Process for the preparation of Donepezil Intermediate"
2. Applicant (s)
(a) NAME: ARCH PHARMALABS LIMITED
(b) NATIONALITY: INDIAN
(c) ADDRESS: "H" Wing, 4th floor, Tex Centre, Off Saki Vihar Road,
Chandivali, Andheri (East), Mumbai-400072, India.
PREAMBLE TO THE DESCREPTION
The following specification particularly describes the invention and the manner in which it is to be performed

Title: Process for the preparation of Donepezil Intermediate
Technical field of the invention
Disclosed herein is an efficient process for the preparation of N-benzyl-4-
formylpiperidine of formula-l which is a Key intermediate for the
preparation of acetylcholinesterase inhibitor Donepezil hydrochloride (Il),
chemically known as (+-)-2, 3-dihydro-5, 6-dimethoxy-2-[[1-(phenylmethyl)-
4-piperidinyl]methyl]-1H-inden-1-one hydrochloride. Donepezil
hydrochloride (Il) is a reversible inhibitor of the enzyme acetylcholinesterase useful in the treatment of mild to moderate dementia of the Alzheimer's type disease.

Background of the invention
US 48,95841 discloses Donepezil hydrochloride (il), chemically known as (±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one hydrochloride, as cyclic amine compounds of formula II.


Donepezil hydrochloride (II) is a reversible inhibitor of the enzyme acetylcholinesterase useful in the treatment of mild to moderate dementia of the Alzheimer's type disease.
N-benzyl-4-formylpiperidine (I) is a key intermediate for the preparation of donepezil.
EP0206560 discloses the preparation of compound of Formula I by using (methoxymethyl)triphenyl phosphonium chloride as a reagent. However, this reagent is not only very expensive, but also requires the reaction to take place under cryogenic conditions.
US4895841 discloses pyridine-4-aldehyde for the preparation of intermediate (I), which is followed by reduction of aromatic ring at the last stage.
US2009187020A1 discloses a process using alkyl chloroacetate as a reagent for the preparation of intermediate of Formula I.
CN1556105 discloses a process for the preparation of compound of Formula I comprising reacting N-benzyl-4-piperidone with thmethylsulfonium iodide (TMSOI) to form 6-benzyl-1-oxa-6-azaspiro[2.5]octane, followed by catalytic rearrangement with magnesium bromide-etherate. Thmethylsulfonium iodide is an expensive reagent and comprises the use of methyl iodide for its preparation which would require special care for handling on industrial scale.
Processes disclosed in the prior art for preparing compound of Formula I and Donepezil thereof comprises of use of trimethylsulfoxonium iodide and thmethylsulfonium iodide as reagents which are not only very expensive

on an industrial scale as raw material which inturn also increases the manufacturing cost of Donepezil, but also not very convenient to use as the process for making trimethylsulfoxonium iodide and trimethylsulfonium iodide requires handling of methyl iodide as a starting material.
There is an urgent need to develop a simple, inexpensive and easy to operate process for the preparation of compound of Formula I which is a key intermediate for the preparation of Donepezil of formula II, which would employ a raw material that could be procured cheaply in large quantities and would minimize the reaction handling aspect of the chemical manufacturing process and also will reduce the cost of manufacturing of donepezil
Object of the invention:
Disclosed herein is a novel process for the preparation of N-benzyl-4-. formyl piperidine of Formula-I which is a key intermediate for the preparation of donepezil hydrochloride. The present invention provides a simple, safe and industrially viable process for the preparation of key intermediate of formula-l. The said intermediate of formula I can be used for the preparation of Donepezil in a cost effective manner avoiding unfavorable reaction conditions.
Present invention relates to the economical and easy to operate process for the preparation of donepezil comprising preparation of epoxide of the formula VI comprising using trimethylsulfoxinium monomethylsulphate Complex of Formula IV or trimethylsulfonium mono methylsulphate Complex of Formula V replacing trimethylsulfoxinium iodide and trimethylsulfonium iodide disclosed hereinbefore in the prior art. The epoxide so formed undergoes a rearrangement in presence of BF3

etherate producing the intermediate of the formula I which can be converted further into donepezil.
According to one aspect there is provided a process for the preparation of compound of Formula I.
According to another aspect there is provided a process for preparing a compounds of formula VI
According to yet another aspect there is provided a process for preparing compound of formula IV
According to still another aspect there is provided a process for preparing a compound of formula V
According to still yet another aspect there is provided a process for making Donepezil and its pharmaceutically active salts using compound of formula I as an intermediate prepared by the process disclosed herein in the present invention.
Summary of the invention
Disclosed herein is a process for preparing a compound of formula I


Comprising contacting a compound N-benzyl-4- piperidone of Formula III

with trimethylsulfoxinium monomethylsulphate Complex of Formula IV or trimethylsulfonium monomethylsulphate Complex of Formula V

in a suitable solvent in the presence of a base to give a compound of Formula VI


which is contacted with BF3.OEt2 in a suitable solvent in the presence of an acid to give a compound of Formula 1.
" The compound of formula I obtained hereinabove can be converted into Donepezil and its pharmaceutically active salts.
The term contacting herein means dissolving, slurring, stirring and the like or combination thereof.
The process of the present invention is represented in schemes -1 and 2 given hereinbelow:
Scheme-1

Detailed Description
Reference will now be made in detail to the preferred embodiments of the invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. In addition, and as will be appreciated by one of the skill in the art, the invention may be embodied as a method, system or process.
In an embodiment disclosed herein is a process for the preparation of N-benzyl 4-formyl piperidine of formula I which is used as an intermediate for the preparation of donepezil and salts thereof. Process disclosed herein comprises contacting N-benzyl- 4- piperidone of formula III

With trimethylsulfoxonium monomethylsulphate complex of Formula IV in a suitable solvent at a temperature about 5°C to about 65°C in about 0.5 to about 5 mole ratio

in the presence of a base to obtain a compound of formula VI


The solvent employed for this reaction is selected from alcohols, esters, ethers .hydrocarbons and the likes or mixture thereof. Preferably solvent is ether and more preferably the solvent is THF.
Base employed for this reaction is selected from alkali metal hydroxides, alkali metal alkoxides, metal hydrides, alkali metal amides, alkyl lithium, tetraalkylammonium hydroxides and the likes. Preferably base is selected from alkali metal alkoxides. More preferably base is sodium methoxide.
The compound of formula VI is contacted with Lewis acid or Bronsted acid in a suitable solvent to obtain a compound of formula I which inturn can be converted into Donepezil and salts thereof.
The Lewis acid or Bronsted acid employed for this reaction is selected from LiCI, resin, AICI3, MgCI2, LiBr, PTSA.H20, trimethyl borate, Aq. HCI,

CeCI3, Fused ZnCI2, anhy. ZnCI2, NH4CI, TiCI4, Sodium metabisulfite, Sodium metabisulfite & H2S04, MgBr2.Et20, BF3.Et20 and the likes. Preferably lewis acid or Bronsted acid is selected from MgBr2. Et20, BF3.Et20 and more preferably lewis acid is BF3.Et20. The solvent employed for the said reaction is selected from hydrocarbons, halogenated hydrocarbons, ethers, water or mixture thereof. Preferably solvent is selected from aromatic hydrocarbons. More preferably solvent is toluene.
Trimethylsulfonixium monomethylsulphate of formula IV is prepared by the process disclosed herein before in the prior art reference JP-08- 012750 • comprising reacting dimethyl sulfate with dimethyl sulfoxide in equimolar ratio replacing use of trimethylsulfonium iodide which is very expensive and also not easy to use at an industrial scale as it comprises use of methyl iodide for its preparation as disclosed in CN1556105.
Process for the preparation of compound of formula I which is a key intermediate for the preparation of donepezil comprising use of compounds of formulae IV or V as raw material which themselves comprise the use of economical, safe and easily available starting materials like dimethyl sulphate, dimethyl sulphoxide or dimethyl sulphide overcome the disadvantages of the processes disclosed in the prior art - hereinbefore for the preparation of compound of formula I by replacing trimethylsulphonium iodide and trimethylsulfoxonium iodide which comprises .use of methyl iodide as a starting material which is more expensive and being low boiling is unsafe, therefore, requires special handling precautions at industrial scale.
In an embodiment disclosed herein is a process for the preparation of N-benzyl-4-formylpiperidine of formula I which is used as an intermediate for the preparation of Donepezil and salts thereof. Process disclosed herein comprises contacting N-benzyl- 4- piperidone of formula III

Formula III With trimethylsulfoxonium monomethylsulphate complex of Formula IV in a suitable solvent at a temperature about 5°C to about 65°C in about 0.5 to about 5 mole ratio

in the presence of a base to obtain a compound of formula VI

The solvent employed for this reaction is selected from alcohols, esters, ethers .hydrocarbons and the likes or mixture thereof. Preferably solvent is ether and more preferably the solvent is THF.

Base employed for this reaction is selected from alkali metal hydroxides, alkali metal alkoxides, metal hydrides, alkali metal amides, alkyl lithium, tetraalkylammonium hydroxides and the likes. Preferably base is selected from alkali metal alkoxides. More preferably base is sodium methoxide.
The compound of formula VI is contacted with Lewis acid or Bronsted acid in a suitable solvent to obtain a compound of formula I which intern can be converted into Donepezil and salts thereof.
The Lewis acid or Bronsted acid employed for this reaction is selected from LiCI, resin, AICI3, MgCI2, LiBr, PTSA.H2Of trimethyl borate, Aq. HCI, CeCI3, Fused ZnCI2, anhydrous. ZnCI2, NH4CI, TiCI4, Sodium metabisulfite, Sodium metabisulfite & H2S04, MgBr2.Et20, BF3.Et20 and the likes. Preferably Lewis acid or Bronsted acid is selected from MgBr2. Et20, BF3.Et20 and more preferably Lewis acid is BF3.Et.2O. The solvent employed for the said reaction is selected from hydrocarbons, halogenated hydrocarbons, ethers, water or mixture thereof. Preferably solvent is selected from aromatic hydrocarbons. More preferably solvent is toluene.
Trimethylsulfoonium monomethylsulphate complex compound of formula V is prepared by the process disclosed therein before in the reference Synthetic Communications, volume 15, Issue 8, June 1985, Pages 749-757. This circumvents the problem of using trimethylsulfonium iodide disclosed as a reagent for making compound of formula VI.
Process for the preparation of compound of formula I which is a key intermediate for the preparation of Donepezil comprising use of compounds of formulae IV or V as raw material which themselves comprise the use of economical, safe and easily available starting materials like dimethyl sulphate, dimethyl sulphoxide or dimethyl sulphide overcome the disadvantages of the processes disclosed in the prior art

hereinbefore for the preparation of compound of formula I by replacing trimethylsulphonium iodide and trimethylsulfoxonium iodide which comprises .use of methyl iodide as a starting material which is more expensive and being low boiling is unsafe, therefore, requires special handling procedure at industrial scale.
Examples:
The present invention may be illustrated by example. The following Examples illustrate specific embodiments of the present invention. These Examples are only intended to illustrate the present invention and are not intended to limit the scope thereof. Many variations in the process may be made without departing from the spirit and scope of the present invention.
Example-1
Process for the preparation of Trimethylsulfoxonium
monomethylsulfate(IV):
To a 1 L flask equipped with a stirrer, thermometer and calcium chloride
guard tube, 129.2 g Dimethyl sulfate (DMS) (1.025 mol) was added. The
temperature of DMS raised to 105°C. 80 g of dimethyl sulfoxide (DMSO)
(1.025 mol) was added to the stirred DMS solution drop wise in 1 hr. The
reaction mixture was heated at 100°C for another 2 hours and cooled to
ambient temperature to obtain TMSOMS. This can be directly used for
next step.
Example-2
Process for conversion of N-benzyl-4-piperidone to Formula VI using
Trimethylsulfoxonium monomethylsulfate(IV)
In 1L flask equipped with stirrer, thermometer and calcium chloride guard
tube, 100 ml THF was added followed by addition of 18.61g potassium
tert-butoxide (0.166 mol), 32.3 g trimethylsulfoxonium monomethylsulfate
(0.158 mol) and 0.85g Tetrabutylammonium bromide (0.0026 mol) in the

order. After stirring the reaction mixture for 2 hours at 25-30°C1 10 g N-benzyl-4-piperidone (0.053 mol) was added in 5 minutes and stirring continued for another 3 hours. Reaction mixture was poured into 100 ml of water and extracted with dichloromethane (200 ml), organic layer was separated and washed with brine. Solvent was removed from the separated organic layer by distillation to yield 9 g Formula VI (6-benzyl-1-oxa-6-azaspiro[2.5]octane).
The product was analysed by gas chromatography and the retention time was same as that for the authentic sample (6-benzyl-1-oxa-6-azaspiro[2.5]octane) obtained by TMSOI.
Example-3
Process for the preparation of Trimethylsulfonium monomethylsulfate(V) into a 250 mi flask equipped with a stirrer, thermometer and calcium . chloride guard tube, 25 g dimethyl sulphate (DMS) (0.198 mol) was added and cooled to 0°C. 12.28 g of dimethyl sulfide (0.198mol) was added drop wise to the cooled DMS solution. The reaction mixture was stirred at 0°C to 5CC for 1 hour and then at 25-30°C for another 1 hour to obtain 37.28 g of compound of Formula (V) as white solid. This was directly used for the next step.
Example-4
Process for conversion of N-benzyl-4-piperidone to Formula VI using Trimethylsulfonium monomethylsulfate (V)
In 1L flask equipped with stirrer, thermometer and calcium chloride guard • tube, 5 g N-Benzyl-4-Piperidone (0.026 mol) was added. 50 ml THF, 0.44 g TBAB (0.0013 mol) and 7.77 g Potassium tert-butoxide (0.069 mol) were added sequentially at 25-30°C. 12.43 g trimethylsulfonium monomethylsulfate (0.066 mol) was added and the contents of the flask were stirred for another 1 hour. The reaction mixture was poured into 50

ml of water and the aqueous layer was extracted with dichloromethane,
organic layer separated and washed with brine. Solvent was removed by
distillation from the separated organic layer to yield 4.5 g epoxide (6-
benzyl-1-oxa-6-azaspiro[2.5]octane).
This was analysed by gas chromatography and the retention time was
same as that for the authentic sample (6-benzyl-1-oxa-6-
azaspiro[2.5]octane).obtained by TMSOl.
Example-5
Process for conversion of 6-benzyl-1-oxa-6-azaspiro[2.5]octane to N-benzyl-4-formylpiperidine
Into a 2 L 4-neck flask equipped with a stirrer,, thermometer and calcium chloride guard tube, 150 g 6-benzyl-1-oxa-6-azaspiro[2.5]octane (0.739 mol) was added, followed by the addition of 1.5 Lit dichloromethane at 20°C. 115.4 g of BF3.Et20 (0.8128 mol) was added to the above stirred solution drop wise over 30 minutes. After stirring at 25°C for 4 hr., 750 ml of 1 N HCI solution was added slowly and reaction mass was stirred at 25°C for 20 hr. Two layers were allowed to separate and aqueous layer was extracted with dichloromethane (2X150 ml_). The aqueous layer was basified with saturated Na2C03 (300g in 600mL Water) at 30°C and the solution was stirred for 1 hr at 30DC. The aqueous layer was extracted with dichloromethane (4X300 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate. Solvent was removed from organic layer by distillation to yield 132 g of crude product which was then purified by distillation under reduced pressure [B.P. 130-134°C / 1mm Hgj to get colorless oil (N-Benzyl-4-Formyl Piperidine).
The product was analyzed by 1H- NMR and IR

Example -6
1-Benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidenyl-methylpiperidine hydrochloride
This reaction was conducted in an argon atmosphere.
Into a 2 L 4-neck flask equipped with a stirrer, thermometer and calcium chloride guard tube, 2.05 ml of diisopropylamine was added to 10 ml of anhydrous THF, followed by addition of 9.12 ml of a 1.6M solution of n-butyllithlum in hexane at 0° C. The mixture was stirred at 0° C. for 10 min and then cooled to-78° C, and a solution of 2.55 g of 5,6-dimethoxy-1-indanone in 30 ml of anhydrous THF and 2.31 ml of hexamethyl-phosphoric amide were added thereto. The mixture was stirred at-78. degree. C, for 15 min, and a solution of 2.70 g of 1-benzyl-4-piperidinecarboaldehyde in 30 ml of anhydrous THF was added thereto. The temperature of the mixture was gradually raised to room temperature, followed by stirring for 2 hr. An aqueous 1% ammonium chloride solution was added thereto, and the organic phase was separated. The water phase was extracted with ethyl acetate, and the organic phases were combined with each other. The combined organic phase was washed with a saturated saline solution, dried over magnesium sulfate, and concentrated in vacuo. A 10% solution of hydrochloric acid in ethyl acetate was added to the resulting solution, followed by concentration in vacuo to obtain a crystal, which was recrystallized from methanol/IPE to obtain 3.40 g (yield: 62%) of the title compound.

Claims:
1. Process for making of N-benzyl-4-formylpiperidine compound of formula I

a) comprising contacting N-benzyl- 4- piperidone compound of formula III

with trimethylsulfoxonium monomethylsulphate complex of Formula IV in an organic solvent


Formula IV in the presence of a base to obtain a compound of formula VI

b) compound of formula VI obtained in (a) is contacted with a suitable acid selected from Lewis acid or Bronsted acid in an organic solvent to obtain a compound of formula 1.
2. Process of claim 1a wherein organic solvent is selected from from
alcohols, esters, ethers .hydrocarbons or mixture thereof.
3. Process of claim 2 wherein organic solvent is THF.
4. Process of claim 1a wherein base is selected from alkali metal
hydroxides, alkali metal alkoxides, metal hydrides, alkali metal amides,
alkyl lithium, tetraalkylammonium hydroxide, and tetraalkylammonium
alkoxide.
5. Process of claim 4 wherein base is selected from alkali metal alkoxides.
6. The process of claim 5 wherein base is sodium methoxide.

7. Process of claim 1b wherein Lewis acid or Bronsted acid employed for this reaction is selected from LiCI, resin, AICI3, MgCI2, LiBr, PTSA.H2O, trimethyl borate, Aq. HCI, CeCI3, anhy. ZnCI2, NH4CI, TiCI4, Sodium metabisulfite, H2S04, MgBr2. Et20, BF3.Et20 or mixture thereof.
8. process of claim 6 wherein the Lewis acid is BF3.Et20.
9. Process of claim 1b wherein solvent for the said reaction is selected from hydrocarbons, halogenated hydrocarbons, ethers, water or mixture thereof.
10. Process of claim 8 wherein solvent is toluene.
. a) comprising contacting N-benzyl- 4-piperidone compound of formula III

11. Process for making of N-benzyl-4-formylpiperidine compound of
formula I


Formula III
with trimethylsulfonium monomethylsulphate complex of Formula V in an organic solvent

Formula V in the presence of a base to obtain a compound of formula VI

Formula VI b) compound of formula VI obtained in (a) is contacted with a suitable acid selected from Lewis acid or Bronsted acid in an organic solvent to obtain a compound of formula I.
12. Process of claim 11a wherein organic solvent is selected from
alcohols, esters, ethers, hydrocarbons and the likes or mixture thereof.
13. Process of claim 12 wherein organic solvent is THF.

14. Process of claim 1a wherein base is selected from alkali metal
hydroxides, alkali metal alkoxides, metal hydrides, alkali metal amides,
alkyl lithium, tetraalkylammonium hydroxide, and tetraalkylammonium
alkoxide.
15. Process of claim 14 wherein base is sodium methoxide.
16. Process of claim 1b wherein Lewis acid or Bronsted acid employed for this reaction is selected from LiCI, resin, AICI3, MgCI2, LiBr, PTSA.H20, trimethy) borate, Aq. HCI, CeCI3, anhy. ZnCI2, NH4Cl, TiCU, Sodium metabisulfite & H2S04, MgBr2. Et20, BF3.Et20 or mixture thereof.
17. process of claim 16 wherein Lewis acid is BF3.Et20.
18. Process of claim 1b wherein solvent for the said reaction is selected from hydrocarbons, halogenated hydrocarbons, ethers, water or mixture thereof.
19. Process of claim 18 wherein solvent is toluene.