WO2011070585A1

WO2011070585A1 - Processes for preparing rivastigmine, salts and intermediates thereof

Info

Publication number: WO2011070585A1
Application number: PCT/IN2010/000703
Authority: WO
Inventors: Thota Giridhar; Gudipati Srinivasulu; Kotaru Srinivasa Rao
Original assignee: SHODHANA LABORATORIES Ltd
Current assignee: SHODHANA LABORATORIES Ltd
Priority date: 2009-10-28
Filing date: 2010-10-28
Publication date: 2011-06-16
Anticipated expiration: 2012-04-28

Abstract

Processes for preparing Rivastigmine, salts and intermediates thereof are disclosed. More specifically, a process for preparing S-(-)-3-[(l -dimethylamino)ethyl]-phenol is provided.

Description

PROCESSES FOR PREPARING RIVASTIGMINE, SALTS AND INTERMEDIATES THEREOF

FIELD OF THE INVENETION

The present patent application relates to a process for the preparation of nvastigmine, its salts and intermediates thereof. More specifically, it relates to preparation of enantiomerically pure S-(-)-3-(l-dimethylamino) phenol, which is used as an intermediate in the preparation of rivastigmine and its salts.

BACKGROUND OF THE INVENTION

Rivastigmine hydrogentartrate is chemically known as (S)-N-Ethyl-N- methyl-3-[l-(dimethylamino)ethyl]-phenyl carbamate hydrogen- (2R, 3R)- tartrate (hereinafter referred to as "Rivastigmine hydrogentartrate") and has structural Formula I .

Formula I

Rivastigmine hydrogentartrate is administered for the inhibition of reversible cholinesterase and is marketed under the brand name EXELON as capsules containing 0.5, 3, 4.5 and 6 mg rivastigmine base equivalent.

U.S. Patent No. 4,948,807 describes the compound N-ethyl, N-methyl- 3-[l-(dimethylamino) ethyl] phenyl carbamate and its pharmacologically acceptable salts along with a pharmaceutical composition useful for treating anti-cholinesterase activity in humans.

U.S. Patent No. 5,602,176 describes (S)-N-ethyl- N-methyl-3-[(l - dimethylamino) ethyl] - phenyl carbamate in free base or acid addition salt form as useful for its anti-cholinesterase activity. It also describes process for preparation involving resolution of N-ethyl, N-methyl-3-[l- (dimethylamino) ethyl] phenyl carbamate in presence of (+)-di-para-toluoyl tartaric acid ((+)-DPTTA). The yield of the resolution process is very low and resolution with resoluting agents such as (+)-DPTTA is of high cost.

Resolution in the final stage of synthesis has technological disadvantage as at least 50% of the racemic compound (herein (R)-enantiomer of

rivastigmine) represents as useless waste. Since the waste was too big result into high cost, making the process not suitable for commercial

manufacturing.

International Application Publication No WO 04/ 037771 discloses preparation of Rivastigmine by resoluting 3-[(l-dimethylamino) ethylj-phenol with S-(+)-camphor-10-sulfonic acid in presence of ethylacetate to obtain an optically pure S-(-)3-[(l-dimethylamino) ethylj-phenol and converting the same to rivastigmine. The yield of the resolution process is very low and purity of the compound was not detailed. Resolution with S-(+)-camphor-10- sulfonic acid is of high cost, difficult for recovery and does not suit for commercial manufacturing.

US 2008/0255383 Al discloses preparation of rivastigmine by resolution of l-(3-methoxy phenyl)ethylamine with L-(+)-mandelic acid in isopropyl alcohol, reacting the mandelate salt of l-(3-metho y

phenyl)ethylamine with formaldehyde and formic acid to get S-(-)-(l-(3- methoxy phenyl)ethyl) dimethyl amine and converting the same to

rivastigmine. This process involves use of high volume of alcohol solvent making the process not viable for commercial manufacturing.

JP 1106368 A discloses resolution of l-(3-methoxy phenyl) ethylamine with optically active mandelic acid in presence of water in methyl tert- butylether solvent. However the solvent used is volatile and not

recommended for commercial manufacturing.

JP 1003627 A discloses resolution of 1 -(3-methoxy phenyl) ethylamine with optically active N-(p-toluenesulfonyl)-proline in presence of alcohol solvents, ketone solvents or ester solvents. Resolution with optically active N-(p-toluenesulfonyl) -proline is of high cost and not favorable for

commercial manufacturing. Resolution in the final stage of synthesis has technological

disadvantage as at least 50% of the racemic compound represents as useless waste. The waste was much bigger and optical resolution never separate enantiomers quantitatively.

Resolution in early stages of a synthesis appears to be preferable but depends on how it is feasible for further synthesis of the compound without racemizations.

Therefore there is a need for a process, which is advantageous to increase the yields, eco friendly and suitable for commercial manufacturing.

SUMMARY OF THE INVENTION

The present patent application relates to a process for the preparation of rivastigmine, its salts and intermediates thereof.

In one aspect the present application provides a process for the preparation of S-(-)-3-[(l-dimethylamino) ethyl]-phenol of Formula II comprising the steps of:

a) reacting l-(3-methoxy phenyl) ethylamine of Formula III with L-(+)- mandelic acid in an ester solvent to form a diastereomeric salt of Formula IV, wh -(+)-mandelic acid;

Formula III Formula IV b) reacting the diastereomeric salt of Formula IV, with methylating agent to form S-(-) - (l-(3-methoxy phenyl)ethyl) dimethyl amine of Formula

V; and

Formula V

c) reacting S-(-)-(l-(3-methoxy phenyljethyl) dimethyl amine of

Formula V with hydrobromic acid to obtain S-(-)-3-[(l-dimethylamino) ethyl]- phenol of Formula II.

Formula II

In a related aspect, the present application also provides a process for purification of S-(-)-3-[(l-dimethylamino) ethylj-phenol of Formula II in a chlorohydrocarbon solvent.

In another aspect, the present application also provides a process for purification of l-(3-methoxy phenyl) ethylamine L-(+)-mandelic acid salt of Formula IV in an ester solvent.

In yet another aspect, the present application relates to the process for the preparation of 3-((S)-l-aminoethyl)phenol compound of formula VII comprising,

a) the reaction of diastereomeric compound of formula IV with a base to obtain compound of formula VI,

b) and reacting the compound of formula VI with Hydrobromic acid to obtain the compound of formula VII.

Formula VI, Formula VII.

In a further aspect, the present application relates to the process for preparing rivastigmine or its pharmaceutically acceptable salt comprising the reaction of S-(-)-3-[(l-dimethylamino) ethylj-phenol of Formula II with N- methyl, N-ethyl carbamoyl chloride in the presence of an alkali metal hydroxide.

The present patent application also related to use of S-(-)-3-[(l- climethylamino) ethylj-phenol of Formula II, l-(3-methoxy phenyl)

ethylamine L-(+)-mandelic acid salt of Formula IV, S-(-) - (l-(3-methoxy phenyl)ethyl) dimethyl amine of Formula V, (S)-l-(3- methoxyphenyl)ethanarnine of formula VI and 3-((S)-l-aminoethyl)phenol of formula VII obtained by the process of present application, in the

preparation of rivastigmine or a salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect the present application provides a process for the preparation of S-(-)-3-[(l-dimethylamino) ethylj-phenol of Formula II comprising the steps of:

V; and

Formula V

c) reacting S-(-)-(l-(3-methoxy phenyl)ethyl) dimethyl amine of

Formula V with hydrobromic acid to obtain S-(-)-3-[(l-dimethylamino) ethylj- phenol of Formula II.

Formula II Step a) involves reacting l-(3-methoxy phenyl) ethylamine of Formula ΙΠ with L-(+)-mandelic acid in an ester solvent to form a salt.

Suitable ester solvent for conducting the reaction includes

ethylacetate, n-propylacetate, isopropylacetate, butyl acetate and ethyl butyrate or their mixtures with water. The preferable solvent is aqueous ethylacetate.

Suitably the volume of solvent used in reaction may be from about 5 times to about 30 times, preferably for about 15 times to the weight of l-(3- methoxy phenyl) ethylamine of Formula ΙΠ.

Suitable temperature for conducting the reaction can range from about 20°C to about reflux temperature of the solvent used, preferably 25- 35°C.

The reaction may be carried out for about 30 minutes to about 5 hours, preferably for about 30-60 minutes.

The diastereomeric salt of Formula IV may be isolated by suitable techniques such as filtration by gravity, or by suction, centrifugation and the like.

If required, the diastereomeric salt of Formula IV may be further purified by any process including the process described in this application.

The diasteromeric salt obtained in step a) may be further dried. Drying may be suitable carried out in a tray drier, vacuum oven, fluidized bed drier and spin flash drier.

In one embodiment, the present application also provides a process for purification of l-(3-methoxy phenyl) ethylamine L-(+)-mandelic acid salt of Formula IV in an ester solvent.

Suitable ester solvent for conducting purification includes

ethylacetate, n-propylacetate, isopropyl acetate, butyl acetate and ethyl butyrate or their mixtures with water. The preferable solvent is aqueous ethylacetate (1:1).

Suitably the volume of solvent used in purification may be from about 3 times to about 6 times, preferably for about 4 to 5 times to the weight of wet l-(3-methoxy phenyl) ethylamine L-(+)-mandelic acid salt. The reaction mixture may be heated to reflux temperature of the solvent used and stirred for about 30 minutes to 1 hour. Then the reaction mixture may be cooled to room temperature for complete solid separation.

The purified diastereomeric salt of Formula IV may be isolated by suitable techniques such as filtration by gravity, or by suction,

centrifugation and the like.

Step b) involves reaction of the diastereomeric salt of Formula IV with a methylating agent to obtain S-(-)-(l-(3-methoxy phenyl)ethyl) dimethyl amine of Formula V.

The diastereomeric salt of Formula IV obtained in step a) may be directly used in the step b) or it may be converted to free base by

conventional processes. In one specific embodiment, the diastereomeric salt of Formula IV obtained in step a) is directly used in the step b) without converting to freebase.

Suitable methylating regent that may be used in the process of step b) includes dimethylsulfate, methyl bromide, methyl iodide, mixture of formaldehyde and formic acid. The preferable methylating reagent is mixture of formaldehyde and formic acid.

Suitable temperature for conducting the reaction can range from about 80-120 °C, most preferably at about 95-100 °C.

The reaction may be carried out for about 2 to about 10 hours, preferably for about 6-8 hours.

After completion, the reaction mixture may be quenched with water; reaction mixture is washed with toluene. The aqueous layer may be basified and extracted with a suitable solvent such as ethyl acetate. The organic layer containing the product may be directly used in the next step or distilled off completely to obtain residue.

Step c) involves reaction S-(-)-(l-(3-methoxy phenyl) ethyl) dimethyl amine of Formula V with hydrobromic acid to obtain S-(-)-3-[(l- dimethylamino) ethylj-phenol of Formula II.

Hydrobromic acid that may be used in step c) includes gaseous, aqueous or acetic acid hydrobromic acid. Preferably about 40% w/ v to about 48% w/v aqueous hydrogen bromide is used in the reaction. Suitable temperature for conducting the reaction may range from about 90-120°C.

After completion, the reaction mixture may be quenched with water; reaction mixture is washed with toluene. The aqueous layer may be basified and extracted with a suitable solvent such as ethyl acetate. The organic layer containing the product may be directly used in the next step or distilled off completely to obtain solid. The obtained solid may be isolated by slurry in a non-polar solvent such as n-hexane, cyclohexane, petroleum ether and the like.

In a related aspect, the present application also provides a process for purification of S-(-)-3-[(l-dimethylamino) ethyl]-phenol of Formula II in a chlorohydrocarbon solvent.

Suitable chlorohydrocarbon solvent includes dichloromethane. S-(-)-3- [(1-dmiethylarnino) ethyl]-phenol of Formula II solid is recrystallized from dichloromethane by conventional process such as described in Example 5.

a) converting the diastereomeric compound of formula IV to (S)-l-(3- methoxyphenyl)ethanamine the compound of formula VI in a conventional method,

b) and reacting the compound of formula VI with Hydrobromic acid to obtain 3-((S)-l-aminoethyl)phenol the compound of formula VII.

Formula VI, Formula VII.

Step a) involves conversion of the diastereomeric compound of formula IV to (S)-l-(3-met±ioxyphenyl)ethanamine the compound of formula VI in a conventional method. Step b) reacting the compound of formula VI with Hydrobromic acid to obtain 3-((S)-l-aminoethyl)phenol the compound of formula VII similar to the process described in step c) of the first aspect of the invention.

In a further aspect, the present application relates to the process for preparing rivastigrnine or its pharmaceutically acceptable salt comprising the reaction of S-(-)-3-[(l-dimethylamino) ethylj-phenol of Formula II with N- methyl, N-ethyl carbamoyl chloride in the presence of an alkali metal hydroxide.

Suitable solvent that may be used in the reaction include polar aprotic solvents such as dimethylformamide(DMF), dimethylacetamide(DMAC), dimethylsulfoxide(DMSO) and the like; aromatic hydrocarbons such as toluene, xylene and the like; tetrahydrofuran (THF), acetonitrile and the like.

Suitable alkali metal hydroxide that may be used in the reaction includes sodium hydroxide, potassium hydroxide and the like. The reaction is preferably conducted in the presence of nitrogen atmosphere.

N-methyl, N-ethyl carbamoyl chloride is slowly added to the reaction mixture to avoid exothermic reaction.

After completion of the reaction, the product is recovered by

conventional techniques including the process described in Example 6.

Rivastigrnine base obtained by the process of present application is substantially pure and having a purity of more than 99 %, preferably 99.5% as determined by HPLC.

Rivastigrnine base may be reacted with a pharmaceutically acceptable acid to form a corresponding salt.

Suitable pharmaceutically acceptable acids include hydrobromic acid, hydrochloric acid, and organic acids such as acetic acid, succinic acid, oxalic acid, tartaric acid, formic acid, and maleic acid. Preferable acid is L(+) tartaric acid.

Suitably, the solvent employed is a lower alkanol, such as methanol, ethanol or isopropanol; ketone solvents such as acetone, methyl ethyl ketone or methyl isobutyl ketone. Preferable solvent is acetone.

The product obtained may be further dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at temperatures of about 35° C to about 70° C with or without vacuum. The drying can be carried out for any desired time periods to achieve the desired product purity, time from about 1 to 20 hours frequently being appropriate.

The process described herein yields substantially pure rivastigmine hydr ogentartrate .

The present patent application also related to use of S-(-)-3-[(l- dimethylarnino) ethyl]-phenol of Formula II, l-(3-methoxy phenyl)

ethylarnine L-(+)-mandelic acid salt of Formula IV, S-(-) - (l-(3-methoxy phenyl)ethyl) dimethyl amine of Formula V, (S)-l-(3-methoxyphenyl) ethanamine of formula VI and 3-((S)-l-aminoethyl)phenol of formula VII obtained by the process of present application, in the preparation of rivastigmine or a salt thereof.

The process of the present invention is simple and convenient for commercial manufacturing.

Having thus described the invention with reference to particular preferred embodiments and illustrative example, those in the art may appreciate modification to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The examples are set for to aid in understanding the invention but are not intended to, and should not be construed to limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well know to those of ordinary skill in the art and are described in numerous publications. All references mentioned herein are incorporated in their entirety.

EXAMPLES

Example 1; Preparation of S-(-)-l-(3-methoxyphenyl) ethanamine (+)- mandelic acid

50 gm of (±)-l-(3-methoxyphenyl)ethanamine was dissolved in ethylacetate (500 ml)and 50 gm of L (+) -mandelic acid was added to the solution. The reaction mixture was stirred for 30 minutes at 25-35°C. 100 ml of water was added the reaction mixture and heated to reflux. The reaction mixture was stirred for about 20 minutes at reflux and then cooled to 25-35°c. The solid was filtered and washed with 25 ml of ethylacetate to get 43 gm of wet solid.

The wet solid was added to a mixture of ethylacetate (86 ml) and water (86 ml) in another flask. The reaction mixture was heated to reflux and stirred for about 20 minutes at reflux. The reaction mixture was cooled to 25-35°C and stirred for 1 hour. The solid was filtered and washed with ethylacetate (10 ml) to obtain 20 gm of title compound.

R-isomer content by HPLC: Not detected

Example 2: Preparation of S-(-)-l-(3-methoxyphenyl) ethanamine (+)- mandelic acid

50 gm of (±)-l-(3-methoxyphenyl)ethanamine was dissolved in ethylacetate (750 ml)and 50 gm of L (+)-mandelic acid was added to the solution.. Heat the reaction mass to reflux for 30-45 rnin and the reaction mixture was stirred for 30 minutes at 25-35°C. The solid was filtered and washed with 50 ml of ethylacetate to get 150 gm of wet solid.

The wet solid was added to a mixture of ethylacetate (350 ml) and water (350 ml) in another flask. The reaction mixture was heated to reflux and stirred for about 20 minutes at reflux. The reaction mixture was cooled to 25-35°C and stirred for 1 hour. The solid was filtered and washed with ethylacetate (10 ml) to obtain 56 gm of wet solid. The wet solid was dried to get 30 gm of title compound.

R-isomer content by HPLC: 0.15 %

Example 3; Preparation of S-(-)-( l-(3-methoxy phenyl)ethyl) dimethyl amine

30 gm of solid obtained in Example 2, 26.88 gm of paraformaldehyde, and 21.87 gm of formic acid was charged in a flask containing 150 ml of water. The reaction mixture was heated to reflux and stirred for about 8 hours at reflux. After completion of the reaction, cooled the reaction mixture to 25-35°C and washed with toluene (50 ml X 3). The aqueous layer was separated and 15 ml of 40 % aqueous sodium hydroxide solution was added. The reaction mixture was extracted with ethylacetate (100 ml X 1, 50 ml X 2). The total ethyl acetate organic layer was washed with 10% aqueous NaCl solution (100 ml). Finally the organic layer was distilled off completely to obtain 16 gm of the title compound as residue.

Example 4; Preparation of S- (- )- 3- [( 1 -dimethylamino) ethyl]-phenol

15 gm of the residue obtained in Example 3 was charged in a flask containing 84 ml of 48% aqueous hydrogen bromide solution and heated to about 100-110°C. The reaction mixture was stirred for about 10 hours at reflux. After completion of the reaction, the reaction mixture was cooled to 25-35°C and quenched into 150 ml of water. The reaction mass was basified with 60 ml of 40 % aqueous sodium hydroxide solution. The reaction mixture was extracted with ethylacetate (75 ml X 1, 50 ml X 2). The total ethyl acetate organic layer was washed with 10% aqueous NaCl solution (75 ml). Finally the organic layer was treated with activated charcoal and then distilled off completely under vacuum. 5 ml of n-hexane was added to the residue and distilled off completely. Another 30 ml of n-hexane was added to the reaction mixture and stirred for about 1 hour at 25-35°C. The solid was filtered and washed with hexane (5 ml) to obtain 12 gm of the title

compound.

R-isomer content by HPLC: 0.14%

Example 5; Purification of S-(-)-3-[( 1-dimethylamino) ethyl]-phenol

5 gm of S-(-)-3-[(l-dimethylamino) ethylj-phenol obtained in Example 4 was charged with 15 ml of dichloromethane, heated to reflux and stirred for about 45 minutes under reflux. The reaction mixture was then cooled to 25-35°C and maintained for about 30 minutes. The reaction mixture was further cooled to 0-5°C and stirred for about 45 minutes. The solid was filtered and washed with dichloromethane (2 ml) to obtain the title compound (4 gm).

R-isomer content by HPLC: 0.05% Example 6; Preparation of Rivastigmine

25 gm of S-(-)-3-[(l-dimethylamino) ethylj-phenol was dissolved in 250 ml of THF and 12.5 gm of KOH was charged in a flask and stirred for 10 minutes. The reaction mixture was cooled to 10-15°C under nitrogen atmosphere. 25 gm of N-methyl, N-ethyl carbamoyl chloride was added slowly for about 30 minutes and then stirred for 30 minutes. The reaction mixture temperature was allowed to 25-35° and stirred for about 5 hours. The reaction mixture was charged into a flask containing 200 ml of water which is cooled to 0-5°C. The reaction mixture was extracted with toluene (200 ml). Total organic layer was extracted with 20 % aqueous HCl solution. The aqueous layer pH was adjusted to about 10 using aqueous sodium hydroxide solution. The aqueous layer was extracted with dichloromethane (200 ml). The total dichloromethane layer was washed with water and distilled off completely to get 34 gm of rivastigmine base.

Example 7; Preparation of Rivastigmine hydrogentartrate salt

170 ml of acetone was added to the above obtained residue and stirred for dissolution. 20.4 gm of L(+) tartaric acid was added to the solution, heated to about 50 °C and stirred for about 30 minutes. The reaction mixture was cooled to 25-35 °C and stirred for 30 minutes. The reaction mixture was further cooled to 0-5 °C and stirred for 30 minutes. The solid was filtered and washed with acetone (20 ml). The solid was dried at 50-60°C to obtain 46 gm of the title compound.

Purity by HPLC: 99.84 %

Example 8; Preparation of (S)-l-(3-methoxyphenyl)ethanamine

50 gm of (S)-l-(3-methoxyphenyl)ethanamine L-(+)- mandelic acid salt, 200 ml of ethylacetate and 300 ml of water was charged in the round bottom flask. The reaction mixture pH was adjusted to about 9-10 with 40% aqueous sodium hydroxide and stirred for 30 minutes for complete dissolution. The ethylacetate layer was separated and extracted the aqueous layer twice with ethylacetate (100 ml, 50 ml). The total organic layer was washed with water (75 ml), salt water (75 ml) and dried over vacuum salt. The final organic layer was separated and distilled off completely under vacuum to obtain 12.4 gm of the title compound as crude.

Example 9: Preparation of 3-((S)- l-aminoethyl)phenol

About 12 gm of residue obtained in the example 8 was charged with 60 ml of 48% aqueous HBr solution in a round bottom flask and stirred for 10 min. The reaction mixture was heated to reflux at 125-135°C and maintained for 12-14 hours. After completion of the reaction, the reaction mixture was cooled to 25-35 °C. The reaction mixture was washed with toluene (3X10ml). Water (10 ml) was added to the reaction mixture and cooled to 0-5°C, under cooling adjust the pH to 10-12 with caustic lye (22 ml) for the material formation and stirred for 1 hour, filtered and washed with water (10 ml) and dried to obtain 8.2 gm of the title compound as dry compound.

Claims

1. A process for the preparation of S-(-)-3-[(l-dimethylamino) ethyl]- phenol of Formula II comprising the steps of:

a) reacting l-(3-methoxy phenyl) ethylamine of Formula III with L-(+)- mandelic acid in an ester solvent to form a diastereomeric salt of Formula IV, wherein LMA is L-(+) -mandelic acid;

V; and

c) reacting S-(-)-(l-(3-methoxy phenyl)ethyl) dimethyl amine of

Formula V with hydrobromic acid to obtain S-(-)-3-[(l-dimethylamino) phenol of Formula II.

2. The process of claim 1, wherein, the ester solvent includes

ethylacetate, n-propylacetate, isopropylacetate, butyl acetate and ethyl butyrate or their mixtures with water.

3. The process of claim 1, wherein the volume of solvent used in reaction is from about 5 times to about 30 times to the weight of l-(3-methoxy phenyl) ethylamine of Formula III.

4. The process of claim 1 , wherein temperature for conducting the reaction is from about 20°C to about reflux temperature of the solvent used.

5. The process of claim 1 further comprises purification of the

diastereomeric salt of Formula IV by any process including the process described in this application.

6. The process of claim 1 , wherein diastereomeric salt of Formula IV obtained in step a) is directly used in the step b) without converting to freebase.

7. The process of claim 1, wherein the methylating reagent used in the process of step b) includes dimethylsulfate, methyl bromide, methyl iodide, mixture of formaldehyde and formic acid.

8. The process of claim 1 , wherein Hydrobromic acid that is used in step c) includes gaseous, aqueous or acetic acid hydrobromic acid.

9. The process of claim 1, wherein diastereomeric salt of Formula IV obtained in step a) is used in the preparation of (S)-l-(3-methoxyphenyl) ethanamine of formula VI and 3-((S)-l-aminoethyl)phenol of formula VII.

10. A process for purification of S-(-)-3-[(l-dimethylamino) ethyl]-phenol of Formula II comprising recrystallization in a chlorohydrocarbon solvent.

11. The process of claim 10, wherein the chlorohydrocarbon solvent includes dichloromethane.

12. A process for purification of l-(3-methoxy phenyl) ethylamine L-(+)- mandelic acid salt of Formula IV comprising treating with an ester solvent.

13. The process of claim 12, wherein the ester solvent for conducting purification includes ethylacetate, n-propylacetate, isopropyl acetate, butyl acetate and ethyl butyrate or their mixtures with water.

14. The process of claim 12, wherein the ester solvent for conducting purification includes aqueous ethylacetate (1: 1).

15. A process for preparing rivastigmine or its pharmaceutically

acceptable salt comprising the reaction of S-(-)-3-[(l-dimethylamino) ethyl]- phenol of Formula II with N-methyl, N-ethyl carbamoyl chloride in the presence of an alkali metal hydroxide.

16. The process of claim 15, wherein the solvent used in the reaction include polar aprotic solvents such as dimethylformamide(DMF),

dimethylacetamide(DMAC), dimethylsulfoxide(DMSO) and the like; aromatic hydrocarbons such as toluene, xylene and the like; tetrahydrofuran fTHF), acetonitrile.

17. The process of claim 15, wherein the alkali metal hydroxide that may be used in the reaction includes sodium hydroxide, potassium hydroxide.