FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)
"IMPROVED PROCESS FOR CHIRAL SYNTHESIS OF (S)-RIVASTIGMINE AND ITS PHARMACEUTICALLY ACCEPTABLE
SALTS"
UN1CHEM LABORATORIES LIMITED, A COMPANY REGISTERED UNDER
THE COMPANIES ACT; 1956, HAVING ITS REGISTERED OFFICE LOCATED AT
UNICHEM BHAVAN, PRABHAT ESTATE, OFF S. V. ROAD, JOGESHWARI
(WEST), MUMBAI - 400 102, MAHARASTRA, INDIA
The following specification describes the invention.

IMPROVED PROCESS FOR CHIRAL SYNTHESIS OF (S)-RIVASTIGMINE AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS
FIELD OF INVENTION
The present invention relates to an improved process for the preparation of (S)-Rivastigmine and its pharmaceutically acceptable salts.
BACKGROUND OF THE INVENTION
Rivastigmine, structurally represented as compound (1), (S)-N-ethyl-3-[(l-dimethyl amino)ethyl]-N-methyl phenylcarbamate

is known to possess cholinesterase inhibitor activity and is useful in the treatment of Alzheimer's disease.
US 4948807 (Marta W. Rosin et al, 1988) describes the compound N-ethyl-N-methyl-3-[(l-Dimethylamino)ethyl]phenyl carbamate (Rivastigmine), its pharmacological salts and process for its preparation.
US 5602176 (Albert Enz, 1988) describes enantiomeric form of Rivastigmine i.e. (S)- N-ethyl-N-methyl-3-[(l-Dimethylamino)ethyl]phenyl carbamate, as a free base and its acid addition salt. '176 discloses the preparation of S-isomer of N-ethyl-N-methyl-3-[(l-Dimethylamino)ethyl]phenyl carbamate, by resolution of racemic N-ethyl-N-methyl-3-[(l-Dimethylamino)ethyl]phenyl carbamate, (obtained according to method of US 4948807) by formation of diastereomeric salt with di-O,O'-p-toluoyl tartaric acid mononohydrate and the subsequent precipitation of desired enantiomer by repeated

crystallizations in methanol/water. The desired (S)-isomer is then obtained by partitioning the diastereomeric salt with alkali and ether. This process provides low yield of the desired product isomer of N-ethyl-N-methyl-3-[(l-Dimethy amino)ethyl]phenyl carbamate.
US 7544840 (Hana Stepankova et al, 2003) describes a process for the preparation of (S)-N-ethyl-N-methyl-3-[(l-Dimethylamino)ethyl]phenylcarbamate, by the reaction of optically active (S)-3-[l-dimethylamino)ethyl] phenol with carbamoyl halide using strong base like sodium hydride or butyl lithium. The optically active (S)-3-[l-dimethylam'ino)ethyl] phenol is obtained by resolution of the corresponding racemic amine with optically active acid, (S)-(+)-Camphor-10-sulphonic acid. The main drawback of this process are low yields obtained during the resolution of (S)-3-[l-dimethylamino)ethyl phenol and repeated crystallizations to get optically pure compound. Also, the use of base such as sodium hydride on industrial scale is not only hazardous, but also operationally difficult due to its pyrophoric and reactive nature.
EP 1939172 (Murillo Garrido et al, 2005) discloses another alternative method for producing Rivastigmine by reacting (S)-3-[l-methylamino)ethyl] phenol with carbomyl haiide to form an intermediate, which is subjected to reductive amination reaction or methylation reaction by reacting the intermediate with methyl halide to obtain Rivastigmine. The process of preparation of (S)-3-[l-methylamino)ethyl] phenol involves the resolution of racemic 3-[l-methylamino)ethyl] phenol or dealkylation of (S)-l-(3-Methoxyphenyl)ethylmethylamine. The diastereomeric salts of racemic l-(3-Methoxyphenyl)ethylmethylamine are prepared by reacting the corresponding enantiomers of the enantiomeric mixture with a optically active acid, D-(-)-Tartaric acid, recrystallising the diastereomeric salts and obtaining the S-enantiomer by further treatment with a base. '172 process requires additional crystallization steps to obtain tartarate salt with a yield of 27% only. Further, the process involves the use of carcinogenic and toxic methyl iodide.

WO2005/058804 (Fieldhouse, Robin et al, 2003) describes a process for the preparation of chiral tertiary amines having chiral carbon center, which includes Rivastigmine and involves stereo selective reduction of ketones. The chiral hydroxy compounds obtained by stereo selective reduction of ketone are activated and further reacted with amines to get the desired product. The reported advantage is in avoiding the formation of undesired (R)-isomer in terms that only the desired isomer is formed in stereo selective reduction. However, the process involving stereo selective reduction employs the use of chiral coordinated transition metal complex as reagents for catalyzing the hydrogenation..These chiral coordinated transition metal complexes are very expensive and thereby make the process uneconomical on industrial scale. Also, the yield reported for the stereo selective reduction of ketone is only 95%, which further renders the process industrially uneconomical.
WO 2006048720 (Gharpure, Milind, Moreshwar et al, 2004) discloses the resolution of 3-[l-dimethylamino)ethyl phenol using D-(+)-10-Camphor sulphonic acid to obtain its diastereomeric salt with a yield of only 25-30%.
WO2005061446 (Gaitonde. Abhay et al, 2003) discloses the process for preparing Rivastigmine tartrate which involves the use of reagent such as sodium cyanoborohydride, followed by addition of DPTTA and repeated crystallizations to obtain rivastigmine- The drawback of this process is, that it is not industrially economical. In another alternate disclosed in '446 for preparing rivastigmine, involves the use of corrosive reagents such as phosphorus tribromide which is not environmental friendly.
The processes disclosed in above mentioned prior art for preparing Rivastigmine or its pharmaceutically acceptable salt appears industrially not feasible and cost effective for mentioned drawbacks.
Therefore, in order to get the maximum yield during the preparation of Rivastigmine and its pharmaceutically acceptable salts, there is a continuous need for the development of a

cost effective and efficient synthetic route by preparing optically active Rivastigmine intermediates and hence chiral Rivastigmine.
OBJECT OF THE INVENTION
The object of the present invention is to provide an economically viable and environmental friendly process for the production of (S)-N-ethyl-N-methyl-3-[(l-Dimethylamino)ethyl]phenyl carbamate (Rivastigmine) or its pharmaceutically acceptable salts.
Another object of the present invention is to provide a high yielding and industrially feasible process for producing Rivastigmine or its pharmaceutically acceptable salts, wherein the process provides high yield of the desired product.
Yet another object of the present invention is to provide an improved process for producing Rivastigrnine or its pharmaceutical acceptable salts, wherein the process provides highly pure chiral compounds without multiple purification steps in an environmentally friendly reaction condition.
Another object of the present invention is to directly get the optically active intermediates and avoid formation of the undesired (R) isomer. This leads to high yields of the desired product with considerably less amount of the undesired isomer.
SUMMARY OF THE INVENTION
A first aspect of the invention is to provide process for the preparation of compound of formula (XIV) comprising, reacting compound of formula (XIII) with chiral reducing agent (+)-B-chlorodiisopinocampheylborane (+) (DIP chloride) or (-)-B-chlorodiisopinocampheylborane (-) (DIP chloride) optionally in a suitable solvent,


wherein, R represent hydrogen atom, C1-C3 alkyl group or

Above compound of formula (XIV) is obtain as racemic compound (XIV) or single (R)-enantiomer compound of formula (XlVa) or single of (S)-enantiomer compound of formula (XlVb).

A second aspect present invention provides a commercially viable and industrially feasible process for producing (S)-N-ethyl-N-methyl-3-[(l-Dimethyamino)ethyl]phenyl carbamate (Rivastigmine) of Formula 1 or its pharmaceutically acceptable salts.
A third aspect of the invention is to process for the preparation of rivastigmine compound of formula (I) or its pharmaceutically acceptable salts comprising, the ketone group of 3-Hydroxy acetophenone is first chirally reduced using (+)-B-Chlorodiisopinocamphenylborane (DIP Chloride) solution in heptane to provide the corresponding alcohol compound. (R)-3-(l-Hydroxy-ethyl)phenol (Compound II).


Subsequently (R)-3-(l-Hydroxy-ethyl)phenol (Compound II) is activated with Mesyl chloride (or any other activating group) to give dimesylate, compound of formula (III), that is in-situ reacted with Dimethyl amine gas to give amino mesylate compound of formula (IV).

The mesyl group of compound of formula (IV) is deprotected with aqueous alkali, such as sodium hydroxide or potassium hydroxide to give (S)-3-(l-Dimethyl amino-ethyl) phenol, compound of formula (V)

and then reacted with N-Ethyl-N-methyl carbomyl chloride (EMCC) to give Rivastigmine compound of formula (I). It is illustrated in scheme A.



Another aspect of the invention is to provide a process for the preparation of rivastigmine compound of formula (1) or its pharmaceutically acceptable salts comprising, the phenolic group of 3-hydroxyacetophenone is protected with any methylating agent like Dimethyl sulphate to give 3-Methoxy acetophenone. compound of formula (VI)

which is chirally reduced using (+)-B-Chlorodiisopinocamphenylborane (DIP Chloride) solution in Heptane to give the corresponding alcohol, 1-(3-Methoxy Phenyl) ethanol, compound of formula (VII)

1-(3-Methoxy Phenyl) ethanol compound of formula (VII) is activated using Mesyl chloride (or any other activating group) to give compound of formula (VIII), which is in-situ reacted with Dimethyl amine in THF to give S-(-)-[l-(3-Methoxy phenyl)ethyl]-dimethyl amine, compound of formula (IX)


The methoxy group of compound of formula (IX) is deprotected with hydrobromic acid to give (S)-3-(l-Dimethyl amino-ethyl)phenol, compound of formula (V)

and it is then reacted with N-Ethyl-N-methyl carbomyl chloride (EMCC) to give Rivastigmine (I) It is illustrated in scheme B.


Another aspect of the invention is to provides a process for the preparation of rivastigmine compound of formula (I) or its pharmaceutically acceptable salts comprising the phenolic group of 3-hydroxyacetophenone. which is first reacted with 25% solution of N-Ethyl-N-methyl carbomyl chloride (EMCC) to give carbamate, compound of formula (X)

The ketone group of compound (X) is chirally reduced using (+)-B-Chlorodiisopinocamphenylborane (DIP Chloride) solution in heptane to give the corresponding alcohol compound of formula (XI).

The alcohol of formula (XI) is activated using Mesyl chloride (or any other activating group) to give mesylate, compound of formula (XII) and is in-situ reacted with Dimethyl amine solution in THF to give Rivastigmine (I) It is illustrated in scheme C.


DETAILED DESCRIPTION OF THE INVENTION:
Reduction of compound of formula (XIII) is carried out in presence of chiral reducing agent such as (+)-B-chlorodiisopinocampheylborane (+) (DIP chloride) or (-)-B-chlorodiisopinocampheylborane (-) (DIP chloride) optionally in a suitable solvent to obtain compound of formula (XIV).
Above compound of formula (XIV) is obtain as racemic compound (XIV) or single (R)-enantiomer compound of formula (XIVa) or single of (S)-enantiomer compound of formula (XIVb).

The (R)-enantiomer of compound of formula (XIVa) is obtained when reaction of compound of formula (XIII) is carried out with (+)-B-chlorodiisopinocampheylborane (+) (DIP chloride) optionally in presence of solvent.
The (S)-enantiomer of compound of formula (XlVb) Iis obtained when reaction of compound of formula (XIII) is carried out with (-)-B-chlorodiisopinocampheylborane (-) (DIP chloride) in presence of solvent.
The solvent used with chiral reducing agent such as (+)-B-chlorodiisopinocampheylborane or (-)-B-chlorodiisopinocampheylborane is organic solvent.

The examples of organic solvent may include but not limited to aromatic hydrocarbons, hydrocarbons, ethers, esters, nitriles solvents or mixtures thereof.
The examples of ether solvents may include but not limited to diethyl ether, n-propyl ether, diisqpropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 1-4-dioxane or mixtures thereof.
The examples of nitrile solvents may include but not limited to acetonitrile, propionitrile or mixtures thereof,
The examples of ester solvents may include but not limited to ethyl acetate, propyl acetate, isopropyl acetate or mixtures thereof.
The examples of aromatic hydrocarbon solvents may include but not limited to hexane, heptane, toluene, ethylbenzene, cumene, 0-xylene, m-xylene, p-xylene or mixture(s) thereof.
DIP chloride may be used as solution in organic solvent in the range of 40-80% more preferably 60% DIP chloride in heptane.
In the reaction scheme. A, compound 3-hydroxyacelophenone is dissolved in tetrahydrofuran (THF) and to this obtained reaction mixture drop wise addition of DIP chloride solution is carried out at the temperature range in between 0-10°C.
The DIP 'chloride used for the reduction of 3-hydroxyacetophenone is (+)-B-chlorodiisop inocamphey1borane.
The aqueous layer washed with toluene and then acidified with concentrated HC1 and extracted with ethyl acetate.

The purification of (R)-3-(l-hydroxy-ethyl) phenol compound of formula (II) may be optionally carried out with alcoholic solvent, aromatic solvent or mixture(s) thereof.
The example of alcoholic solvents may include but not limited to methanol, ethanol, n-propanol, 2-propanol. 2-butanol and combinations thereof.
The examples of aromatic solvents may include but not limited to toluene, ethylbenzene, cumene, 0-xylene, m-xylene, p-xylene or mixture(s) thereof.
The (R)-3-(l-hydroxy-ethyl) phenol compound of formula (II) may be isolation by the steps of filtration, centrifugation, washing, drying or the combination thereof
Mesyl chloride can be used for the activation of (R)-3-(l-hydroxy-ethyl) phenol compound of formula (II) in presnce of base and formation of dimesylate compound of formula (III) and this dimesylate compound of formula (III) is reacted with dimethyl amine to form compound of formula (IV).
The example of base may include but not limited to triethyl amine, trimethyl amine, tributyl amine and n-butyl amine.
Dimethyl amine may used as gas or solution with water, methanol, THF.
The reaction of dimethyl amine with compound of formula (III) is carried out in-situ and obtained product is in the form of (R)-enantiomer.
The deprotection of mesyl group of compound of formula (IV) is carried out in presence of aqueous alkali solution.
The example of aqueous alkali solution is alkali metal hydroxide and example of alkali metal hydroxide may include but not limited to sodium hydroxide, potassium hydroxide.

The reaction of compound of formula (V) with carbamyl halide is in presence of a base in a solvent to obtain rivastigmine compound of formula (I).

The Carbamyl halide may be optionally used as solution with suitable solvent organic solvent selected from aromatic hydrocarbon, chlorinated hydrocarbon, esters, ethers, alcohols, nitriles, amides and mixture thereof. Preferably with 25 % toluene.
The example of organic base may indued but not limited to N,N-dimethylamine, N-ethyl-N-methyl amine, triethylamine, N,N-dimethylbenzylamine, N.N-diethylbenzylamine, N-methyl morpholine, dimethylaminopyridine, pyridine and the like.
The example of inorganic base may indued but not limited alkali or alkaline earth metals hydroxides, carbonate, hydrides, wherein the alkali and alkaline earth metal is selected from lithium, sodium, potassium, calcium, magnesium and the like, Preferably potassium carbonate.
The solvent used herein is selected from aromatic hydrocarbon, straight or branched chain alcohols, chlorinated solvents, ketones, esters, ethers or mixture thereof. Preferbaly acetone.
The obtaine rivastigmine base is obtained may in the form of oil.

The obtained rivastigmine optionally converted into its phamacutically acceptable salts. Preferably tartarate salt.
The rivastigmine tartarate salt may be obtained by adding acetone and tartaric acid to rivastigmine base and get clear solution.
The isolation of rivastigmine tartarate by filtering the reaction mass followed by cocentrating the filtrate under reduced pressure to get rivastigmine tartarate salt.
In the reaction scheme B, the reaction of 3-hydoxyacetophenone is carried out with dimethyl sulphate in presence of base in solvent to obatin 3-meihoxy acaetophenone compound of formula (VI).
The example of base and solvents are described as above.
The chiral reduction of 3-methoxy acetophenone compound of formula (VI) is carried out in presence of DIP chloride in organic solvent to obtian (R)-l-(3-methoxy phenyl)ethanol compound of formula (VII).
The DIP chloride used for the reduction of 3-methoxy acaetophenone compound of formula (VI) is (+)-B-chlorodiisopinocampheylborane.
The (R)-l -(3-methoxy phenyl)ethanol compound of formula (VII) can be obtained by-concentrating organic layer under vacuum to get oil and to obtain oil give methanol and heptane washing. The methanol layer was concentatred under vacuum to give (R)-l-(3-methoxy phenyl)ethanol compound of formula (VII).
Mesylation'of (R)-l-(3-methoxy phenyl)ethanol compound of formula (VII) can be carried out with mesyl chloride in presence of base in organic solvent to obtain mesylate compound of formula (VIII).

The example of organic base and solvent are given as above.
The reaction of mesylate compound of formula (VIII) with diemthyl amine is carried out in-situ in presence of organic solvent.
The examples of organic base are given as above.
To S-(-)-[l-3-methoxy phenyl)ethyl]-dimethyl amine compound of formula (IX) can be obtaine by seperating organic layer after giving water tretment to reaction mixture and extracted with dilute hydrochloric acid.
The S-(-)-[l-3-methoxy phenyl)ethyl]-dimethyl amine compound of formula (IX) can be isolated by distillation.
Deprotection of methoxy group from S-(-)-[l-3-methoxy phenyl)ethyl;]-dimethyl amine compound of formula (IX) can be carried out in presence of acid such as HBr.
The pH of the reaction miture is adjusted to about 9-10 by adding queous ammonia.
Seprating out organic layer and extracted with ethyl acetate under reduced pressure to get compound of formula (V).
The reaction of compound of formula (V) with carbamyl halide is in presence of a base in a solvent to obtain rivasfigmine compound of formula (I).


wherein X represent Chlorine, Bromide atom.
The Carbamyl halide may be used as solution with suitable solvent organic solvent selected from aromatic hydrocarbon, chlorinated hydrocarbon, esters, ethers, alcohols, nitriles, amides and mixture thereof. Preferably with 25 % toluene.
In the reaction scheme C, the reaction of 3-hydroxyacetophenone with carbamyl halide is carried out in presence of a base in a solvent to obtain compound of formula (X).
The chiral reduction of compound of formula (X) is carried out in presence of DIP chloride in organic solvent to obtian compound of formula (XI)
The DIP chloride used for the reduction of compound of formula (X) is (+)-B-chlorodiisopinocampheylborane.
The examples of organic solvent and bases are given as above.
The mesylation of compound of formula (XI) can be carried out with mesyl chloride in presence of base in organic solvent to obtain compound of formula (XII).
The above obtained reaction mass is treated with dimethyl amine solution is organic solvent and seprated out organic layer and acidfied with dilute hydrochloric acid followed by MDC washing.
Rivastigmine compound of formula (I) is isolated by distilling out methylene chloride (MDC) layer.
The obtained rivastigmine compound of formula (I) optionally converted into its pharmaceutically acceptable salt such as tartarate salt

Thus, the present invention employs the use of chiral reducing agent, (+)-B-Chlorodiisopinocamphenylborane (DIP Chloride) solution in the process for preparing optically active intermediates of Rivastigmine, which results in more than 97% enantioselective isomer. The undesired isomer can be removed from the intermediates by solvent recrystallization.
EXAMPLES
The following examples are presented for illustration only, and are not intended to limit the scope of the invention. Scheme A
1) Preparation of (R)-3-(l-Hydroxy-ethyI) phenol (Compound II)
To 250 ml of THF was added 50 g of 3-Hydroxyacetophenone, cooled the reaction mixture to 0-5 °C and 375 ml of 60% (+)-B-Chlorodiisopinocamphenylborane (DIP Chloride) was added drop wise to the reaction mixture at 0-5 °C. After the addition, the reaction mixture was maintained at 5-15 °C till the reaction is complete. After the completion of reaction, NaOH solution (75 g of NaOH dissolved in 500 ml water) was added drop wise and stirred the reaction mixture vigorously for 1 hr. The lower aqueous layer was separated. The aqueous layer was washed with toluene. The aqueous layer was then acidified with coned HC1 (120 ml), extracted with Ethyl acetate and distilled out ethyl acetate to give 50 g of crude (Compound II).
2) Purification of Compound. II
To the above 50 g of crude product, 400 ml mixture of Toluene: Ethanol (9:1) (360 ml Toluene + 40 ml Ethanol) was added and heated the reaction mixture to get a clear solution. Stopped heating the reaction mixture and cooled it to 0 °C. The separated product was separated and dried to get 38 g of pure (Compound II) of chiral purity more than 99.5%.
3) Preparation of (S)-3-(l-Dimethyl amino-ethyl) phenol {Compound V) via di-
mesylate (Compound III) and amino mesylate (Compound IV).

To 200 ml of Ethyl acetate and 74.66 g of Triethylamine, was added 30 g of (R)-3-(l-Hydroxy-ethyl)phenol (Compound II), cooled the reaction mixture to 0 °C, 76 g of Mesyl chloride was added drop wise to the reaction mixture at 0-5 °C for a period of 2-3 hrs, maintained it at 0-5 °C for 30 min, raised the temperature to 20 °C and stirred further for 30 mins. Passed about 80 g of Dimethyl amine gas through the reaction mixture for about 4 hrs at 15-25 °C, stirred the reaction mixture for 16 hrs at 20 °C, 200 ml water was added to it and stirred for 5 mins. The aqueous layer was separated. The organic layer was extracted with 200 ml of dil HC1. The aqueous layer was washed with ethyl acetate. The aqueous layer was basified with Sodium carbonate solution, extracted the product in MDC and distilled out MDC to get ^ 52 g of oil. To the oil, was added a solution of NaOH (87 g of NaOH dissolved in 270 ml water), heated the reaction to 90 °C till a clear solution was obtained, cooled the reaction mixture to 25-30 °C and washed the reaction mixture with 2 x 100 ml of MDC. The aqueous layer was made acidic with 180 ml of concentrated HC1 and washed the aqueous layer with MDC. The aqueous layer was made basic with 50 ml of liq. Ammonia to pH 9-10. Extracted the product with 3 x 200 ml Ethyl acetate, distilled out ethyl acetate under vacuum to get about 28 g of crude product. To the crude product, was added 84 ml of toluene, was heated to 100 °C to get a clear solution. The reaction mixture was cooled to 30-35 °C, further cooled to 0 °C, Filtered the separated product and dried at 45-50 °C under vacuum for 8 hrs to get 25-27 g of Compound V.
4) Preparation of (S)-Rivastigmine tartarate
In a dry 1 lit flask charge 260 ml of Acetone, was added 26 g of Compound V, 65 g of Anhydrous.Potassium Carbonate was added, 107 g of N-Ethyl N-Methyl carbomyl chloride (25% solution in Toluene) was added drop wise to the reaction mixture at 25-30 °C in a period of 1 hr. The reaction mixture was refluxed at 55-60 °C and maintained at reflux for 6 hrs. The reaction mixture was cooled to 30 °C, filtered the reaction mixture, distilled out Acetone from the mother liquor. To the oily residue, was added 50 ml Toluene and acidified the reaction mixture with dil. HC1. Separated the bottom aqueous layer, cooled it to 10-15 °C and basified with Sodium carbonate. Extracted the product in MDC, distilled out MDC to give 38 g of (S)-Rivastigmine base as oil. To this oil, in a 1

lit flask was added 380 ml of Acetone, 22.8 g of L-(+)-Tartaric acid was added and refluxed to get a clear solution. Cooled the reaction mixture to 30 °C. maintained at 30 °C for 2 hrs, filtered the product and dried the product under vacuum for 8 hrs to get 55 g of S-Rivastigmine Tartarate.
Scheme B
1) Preparation of 3-Methoxy acetophenone (Compound VI).
In a 10 lits'RB flask was added 2.0 lit Acetone, 800 g of 3-Hydroxyacetophenone, and 975 g of Anhydrous Potassium carbonate was added to the reaction mixture and charged 815 g of Dimethyl sulphate to the reaction mixture for about 1-1.5 hrs. After complete addition of DMS, heated the reaction mixture to reflux for 2 hrs, cooled the reaction and added 4 lit of water and separated the top organic layer. The aqueous layer was extracted with 800 ml MDC, washed the mixed organic layers with 10% NaOH solution, washed the organic layer with water and distilled out MDC to get 875 g of 3-Methoxy acetophenone (Compound VI).
2) Chiral .reduction of 3-Methoxy acetophenone (Compound VI) to (R)-l-(3-
Methoxy Phenyl) ethanol (Compound VII)
In a 500 ml RB flask, 10 ml THF, 2 g of 3-Methoxy acetophenone (Compound VI) and 15 ml of 60% (+)-B-Chlorodiisopinocamphenylborane (DIP Chloride) were added to the reaction mixture at -25 °C and stirred the reaction mixture till completion. Added 50 ml of 10% NaHCO3 solution, stirred and separated the layers, washed the organic layer with water till neutral pH and concentrated the organic layer under vacuum. The obtained oil was taken in 20 ml of methanol and given heptane washing. The methanol layer was concentrated under vacuum to give (R)-l -(3-Methoxy Phenyl) ethanol (Compound VII).
3) Reaction of (R)-l-(3-Methoxy Phenyl) ethanol (Compound VII) with Mesyl
chloride followed with Dimethylamine to give S-(-)-[l-(3-Methoxy phenyl)ethyl]-
dimethyl amine (Compound IX)

20 g of (R)-l-(3-Methoxy Phenyl) ethanol (Compound VII) was dissolved in 100 ml MDC and to it was added 27 g of Triethyl amine, cooled it to 0 °C, added 23 g of Mesyl chloride and stirred the reaction mixture for 3 hrs to complete the reaction. Added 200 ml of 2 molar solution of Dimethyl amine in THF to the reaction mixture and stirred for 48 hrs. Added 200 ml of water and separated the layers and washed the organic layer with water. The organic layer was extracted with dilute Hydrochloric acid. The aqueous layer was again made basic with NaOH and extracted with MDC. Distillation of MDC gave S-(-)-[!-(3-Methoxy phenyl)ethyl]-dimethyl amine (Compound IX).
4) Preparation of Compound V from (compound IX)
In a 5 lits RB flask, was added 1317 g of 48% HBr and 155.g of S-(-)-[l-(3-Methoxy phenyl) ethyl]-dimethyl amine (Compound IX), heated the reaction mixture to 110 °C. and maintained for 6 hrs. Stopped heating the reaction mixture and cooled to 5-10 °C. Added 775 ml of water and adjust the pH of the reaction mixture to 8-9 using aqueous Ammonia (-800 ml) below 20 °C. 465 ml Ethyl acetate was added, stirred for 30 min and separated the organic layer. To the aqueous layer, was added 600 g of common salt, stirred for 15 mins and extracted with 3 x 310 ml of ethyl acetate. The ethyl acetate layers were combined and distilled out under reduced pressure. To this solid, was added 650 ml of Toluene and heated to 70-75 °C to get a clear solution, the filtrate was cooled to 0-5 °C and maintained for 1 hr. The solid was filtered, washed with chilled toluene and dried in vacuum oven at 75 °C to get 120 g of Compound V.
5) Preparation of (S)-Rivastigmine tartarate
In a dry 1 lit flask, charged 260 ml of Acetone, 26 g of Compound V, 65 g of anhydrous potassium carbonate and 107 g of N-Ethyl N-Methyl carbomyl chloride (25% solution in Toluene) was added drop wise to the reaction mixture at 25-30 °C for a period of 1 hr. The reaction mixture was refluxed at 55-60 °C and maintained for 6 hrs. The reaction mixture was cooled to 30 °C, filtered and acetone was distilled out from the mother liquor. To the oily residue, was added 50 ml of toluene and acidified with dil. HC1. The bottom aqueous layer was separated; the aqueous layer was cooled to 10-15 °C and

basified with sodium carbonate. The product was extracted in MDC and distilled out MDC to give 38 g of (S)-Rivastigmine base as oil. To this oil. in a 1 lit flask was added 380 ml of acetone, 22.8 g of L-(+)-Tartaric acid and heated to reflux to get a clear solution. The reaction mixture was cooled to 30 °C and maintained at 30 °C for 2 hrs. The product was filtered and dried under vacuum for 8 hrs to get 55 g of S-Rivastigmine Tartarate.
Scheme C
1) Reaction of 3-Hydroxy acetophenone with EMCC (Preparation of compound X)
To 1000 ml of Acetone, 200 g of 3-Hydroxy acetophenone and 400 g of potassium carbonate was added. To this, was added 916 g of 25% solution of N-Ethyl N-methyl carbomyl chloride for 30 min. The reaction mixture was heated to reflux for 4 hrs, cooled, the carbonate was filtered and distilled out acetone from the mother liquor to give Compound of formula X.
2) Preparation of Compound XI
20 g of Compound X was taken in 100 ml of THF and chilled to -25 °C. 100 ml of 60% (+)-B-Chlorodiisopinocamphenylborane (DIP Chloride) solution in heptane was added to the reaction mixture for about 1 hr, stirred till the reaction was complete on TLC. After the completion of the reaction, 100 ml of acetone was added and pH was made basic with 500 ml of 10% aqueous sodium bicarbonate solution. The organic layer was separated and concentrated under vacuum. To the oily product, 100 ml of methanol was added and washed with heptane to remove the a-pinene. The methanol layer was concentrated to give compound of formula XI
3) Preparation of S-Rivastigmine
To 40 g of compound of formula XI in 200 ml of MDC, was added 56 g of Triethyl amine, chilled to 0 °C. added 32 g of Mesyl chloride to the reaction mixture and maintained for 3 hrs till the reaction is complete. 500 ml of 10% Dimethyl amine solution in THF was added to the reaction mixture and stirred for 48 hrs. 600 ml water was added to the reaction mixture and separated the layers. The organic layer was acidified by dilute

HC1. The acidified layer was washed with MDC. The aqueous layer containing the product was basified to pH 12 by using dilute NaOH, extracted with MDC and distilled out MDC to give S-Rivastigmine base.
4) Preparation of Tartarate
To 38 g of (S)-Rivastigmine base oil of above step was added 380 ml acetone, 22.8 g of L-(+)-Tartaric acid and heated to reflux to give a clear solution. The reaction mixture was cooled to 30 °C and maintained at 30 °C for 2 firs. The product was filtered and under vacuum for 8 hrs to get 55 g of S-Rivastigmine Tartarate.

We Claim:
wherein,
R represent hydrogen atom, C1-C3 alkyl group or

1. A process for preparing compound of formula (XI Va) or (XlVb) which comprises of, combining compound of formula (XIII) with chiral reducing agent (+)-B-chlorodiisopinocampheylborane ((+) (DIP chloride)) or (-)-B-chlorodiisopinocampheylborane ((-) DIP chloride)) optionally in a suitable solvent.

wherein compound of formula (XlVa) is (R)-enantiomer and compound of formula (XlVb) is (S)-enantiomer.
2. The process according to claim ], chiral reducing agent DIP chloride is used in presence of suitable solvent such as organic solvent selected from group consisting of hydrocarbons, aromatic hydrocarbons, ethers, esters, nitriles solvents or mixtures thereof.
3. A process for preparing rivastigmine compound of formula (I) or its pharmaceutically acceptable salts ,which comprising steps of,
a. reducing 3-hydroxyacetophenone to (R)-3-(l-hydroxy-ethyl)phenol compound of formula (II) in presence of (+) DIP chloride,


b. optionally purifying compound of formula (II) in a solvent,
c. reacting (R)-3-(I -hydroxy-ethyl)phenol compound of formula (II) with mesyl
chloride to provide dimesylate compound of formula (III),

d, converting dimesylate compound of formula (III) into the amino mesylate compound of formula (IV) by reacting with dimethyl amine,

e. deprotecting amino mesylate compound of formula (IV) in presence of aqueous alkali solution to provide (S)-3-(l -dimethyl amino-ethyl) phenol compound of formula (V).

f. reacting (S)-3-(l -dimethyl amino-ethyl) phenol compound of formula (V), with N-ethyl-N-methyl carbamyl chloride to provide rivastigmine compound of formula (I),


g. optionally converting rivastigmine compound of formula (I) into its pharmaceutically acceptable salt.
4. The process according to Claim 3 (b), wherein purification of (R)-3-(l-hydroxy-ethyl) phenol compound of formula (II) is carried out in presence of toluene, ethanol or mixtures thereof.
5. The process according to Claim 3 (e). wherein an aqueous alkali solution is sodium hydroxide or potassium, hydroxide.
6. A process for preparing rivastigmine compound of formula (I) or its pharmaceutically acceptable salts ,which comprising steps of,
a. protecting 3-hydroxyacetophenone with dimethyl sulphate to provide 3-methoxy acelophenone compound of formula (VI),

b. reducing 3-methoxy acetophenone compound of formula (VI) in presence of (+) DIP chloride to produced (R)-l-(3-methoxy phenyl) ethanol compound of formula (VII),


c. reacting (R)-l-(3-methoxy phenyl) ethanol compound of formula (VII) with mesyl chloride to provide mesylate compound of formula (VIII),

d. reacting mesylate compound of formula (VIII) with dimethyl amine in presence of solvent to provide S-(-)-[l-(3-methoxy phenyl)ethyl]-dimethyl amine compound of formula (IX),

e. deprotecting methoxy group of S-(-)-[ 1 -(3-methoxy phenyl)ethyl]-
dimethyl amine compound of formula (IX) in presence of acid to provide (S)-3-(l -dimethyl amino-ethyl) phenol compound of formula (V),

f. reacting (S)-3-(l-dimethyl amino-ethyl) phenol compound of formula (V) with N-ethyl-N-methyl carbamyl chloride to provide rivastigmine compound of formula (I),

g. optionally converting rivastigmine compound of formula (I) into its pharmaceutically acceptable salt.

7. The process according to claim 6 (e) wherein the acid is Hydrobromic acid.
8. A process for preparing rivastigmine compound of formula (I) or its pharmaceutically acceptable salts ,which comprising steps of,
a. Reacting 3-hydroxyacetophenone with N-ethyl-N-methyl carbamyl chloride to provide carbamate compound of formula (X),

b. reducing carbonyl group of carbamate compound of formula (X) in presence of DIP chloride to provide compound of formula (XI),

c. reacting compound of formula (XI) with mesyl chloride to provide compound of formula (XII),

h. reacting compound of formula (XII) with dimethyl amine in presence of solvent to provide rivastigmine compound of formula (I),

i. optionally converting rivastigmine compound of formula (I) into its pharmaceutically acceptable salt.

9. The process according to Claim 3, 6 and 8, wherein solvent used with dimethyl amine is THF.
10. The process according to claim 1, 3, 6 and 8. wherein DIP chloride is used in solid form or in the form of a solution in range of 40-80% in suitable organic solvent.