PREPARATION OF RIVASTIGMINE AND ITS SALTS TECHNICAL FIELD

The present patent application relates to an improved process for the preparation of
rivastigmine.

BACKGROUND

Rivastigmine hydrogen tartrate is chemically known as (S)-N-Ethyl-N-methyl-3- [1-(dimethylamino) ethyl]-phenyl carbamate hydrogen- (2R, 3R)-tartrate (hereinafter referred to as "rivastigmine tartrate") and has structural Formula I.

Formula I Rivastigmine hydrogen tartrate 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-[1-(dimethylamino)ethyl]phenyl carbamate and its pharmacologically acceptable salts along with a pharmaceutical composition useful for treating anticholinesterase activity in humans.

U.S. Patent No. 5,602,176 describes (S)-[N-ethyl-3-[(1-dimethylamino)ethyl]-N-methyl-phenyl carbamate] in free base or acid addition salt form as useful for its anticholinesterase activity.

International Application Publication No. WO 2004/037771 A1 and European Patent 193926 describe a process for the preparation of (S)-3-[1-(dimethylamino)-ethyl]-phenyl-N-ethyl-N-methyl carbamate by the reaction of optically active m-hydroxyphenylethyl dimethylamine with a carbamoyl halide. International Application Publication No. WO 2005/058804 A1 describes a process for the preparation of rivastigmine by stereoselective reduction. International Application Publication No. WO 2005061446 A2 and European Patent 1697313 describe process for preparing an aminoalkyl phenylcarbamate including rivastigmine, comprising the steps of converting a hydroxy phenyl ketone to a phenylcarbamate ketone, and converting the phenylcarbamate ketone to racemic rivastigmine followed by resolution.

Stereo chemical purity is of important in the field of pharmaceuticals where many of the most prescribed drugs exhibit chirality, as the two isomers exhibit different potency. Furthermore optical purity is important since certain isomers may actually be deleterious rather than simply inert. Therefore, there is a need to obtain the desired enantiomer of rivastigmine with a high enantiomeric purity. Additionally in order to achieve a high efficiency of reaction for industrial scale synthesis of rivastigmine, it is necessary to minimize the enantiomeric impurities, and obtain the desired isomer in high yields and a high optical purity.

The present disclosure provides a process to achieve the above-described advantages by carrying out Dutch resolution thereby avoiding decrease in the yield and the enantiomeric purity. Dutch resolution is the term given to the use of mixtures (families) of resolving agents in classical resolutions. Families in general bear strong structural similarity and are stereo chemically homogeneous (homochirality among family members and enantiomeric purity of the components). The obtained diastereomeric salts have diastereomeric excess significantly higher 90-95% than the 20-30% estimated for classical resolutions.

The process of the present disclosure is simple, non hazardous and easily scalable for commercial production and resolution process of the present disclosure is free from the technical problems associated with prior art, and is also cost effective, commercially viable and well suited for industrial scale up.

SUMMARY

In one aspect, the present application provides a process for the optical resolution of racemic or enantiomerically enriched rivastigmine comprising crystallization of racemic or enantiomerically enriched rivastigmine with a mixture of chiral resolving agents.
In another aspect, the present application provides a process for the preparation of (S)-rivastigmine or a pharmaceutically acceptable salt thereof, the process comprising the steps of:

a) reaction of 3-hydroxyacetophenone of formula VIII with N-ethyl-methyl carbamoyl chloride in the presence of a base to give ethyl-methyl-carbamic acid 3-acetyl-phenyl ester of formula VII

b) stereoselective reduction of 3-acetylphenyl ethyl (methyl) carbamate of formula VII in presence of {(S)-Xyl-Binap-RuCI2-(S)-Daipen, base and hydrogen gas pressure to give (R)-3-(1-hydroxyethyl)phenyl ethyl(methyl)carbamate of formula VI

c) reaction of (R)-3-(1-hydroxyethyl)phenyl-ethyl(methyl)carbamate of formula VI with methanesulfonyl chloride in presence of a base to give (R)-1-(3-((ethyl(methyl)carbamoyloxy)phenyl)ethyl methanesulfonate of formula V followed by in situ reaction with dimethylamine to give (S)-rivastigmine

d) the (S)-rivastigmine obtained in step (c) is resoluted using 'Dutch Resolution' to get pure (S)-rivastigmine, and

e) optionally converting the (S)-rivastigmine into pharmaceutically acceptable salt.
In another aspect, the present application provides a process for purification of rivastigmine comprising,

a) treating the crude rivastigmine with a suitable resin in presence of a solvent, and

b) isolating the pure rivastigmine form the mixture.

In another aspect, the present application provides a process for preparation of rivastigmine free base or its pharmaceutically acceptable salt which is free of isomeric and process related impurities.

In another aspect, this application provides rivastigmine or a pharmaceutically acceptable salt thereof, prepared by the processes herein described above, having less than about 0.5 area % of total impurities as measured by gas chromatography (GC) or high performance liquid chromatography (HPLC).

In another aspect, this application provides rivastigmine or a pharmaceutically acceptable salt thereof, prepared by the processes herein described above, having less than about 0.15 area % of any individual impurity as measured by gas chromatography or high performance liquid chromatography.

In another aspect, this application provides rivastigmine hydrogen tartrate having a purity of greater than about 99.8 area % as measured by high performance liquid chromatography.

In another aspect, this application provides rivastigmine hydrogen tartrate having less than about 0.2 area % of total impurities as measured by high performance liquid chromatography.

In another aspect, this application provides rivastigmine hydrogen tartrate having less than about 0.15 area % of any individual impurity as measured by high performance liquid chromatography.

In another aspect, the present application provides a process for preparation of rivastigmine free base or its pharmaceutically acceptable salt which is substantially free of residual solvents.

DETAILED DESCRIPTION

The present application relates to an improved process for the preparation of rivastigmine and salts thereof.

In an embodiment, the present application provides a Dutch resolution process for optical resolution of rivastigmine to get the desired enantiomer of rivastigmine comprising resolution of racemic or enantiomerically enriched rivastigmine in the presence of a mixture of chiral resolving agents to afford the diastereomeric salt of rivastigmine.

The process of Dutch resolution comprises preparation of a solution of racemic or chirally impure rivastigmine followed by treatment with mixture of chiral resolving agents in the presence of a suitable solvent at suitable temperatures to form diastereomeric salt.

Solution of racemic rivastigmine can be prepared by dissolving rivastigmine prepared using any of the processes known in the art.

Suitable mixture of chiral resolving agents which can be used for the process include, but are not limited to chiral agents such as di-O-p-toluoyl-D-tartaric acid, tartaric acid, camphorsulfonic acid, bromocamphorsulfonic acid, or the like.

Suitable mole ratio of mixture of chiral acids used for the Dutch resolution of can range from about 1:0.25, and in one embodiment about 1:0.5 equivalent.

Suitable organic solvents for formation of diastereomeric salt of rivastigmine include alcohols such as methanol, ethanol, isopropyl alcohol, or 1-butanol; ketones such as acetone, methyl isobutyl ketone, or methyl ethyl ketone; halogenated solvents such as dichloromethane, ethylene dichloride, or chloroform; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, t-butyl acetate, or the like; nitrile solvents such as acetonitrile, propionitrile or the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N,N-dimethylacetamide (DMA) or the like; or mixtures thereof in combination with water in various proportions.

In one embodiment suitable solvents that were used in Dutch resolution can be mixture of isopropyl alcohol and water and the ratio is 1:1.

The chiral resolving agent can be added to the solution of racemic rivastigmine at temperatures ranging from about 20°C to about 120°C or about 60°C to about 70°C.
After the addition of the chiral reagent, typically, for the product isolation to occur, the reaction mass may be maintained further at temperatures lower than the reaction temperatures such as for example below about 10°C to about 35°C, for a period of time as required for a more complete isolation of the product. A person skilled in the art can readily determine the exact cooling temperature and time required for complete isolation.

The diastereomeric salt of rivastigmine is isolated from the final mixture by any of the techniques such as filtration by gravity, or by suction, centrifugation, and the like. The crystals so isolated will carry a small proportion of occluded mother liquor containing a higher percentage of impurities. If desired, the crystals can be washed on the filter with a solvent to wash out the mother liquor.

The wet cake obtained in this step may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or the like. The drying can be carried out at temperatures of about 35° C to about 70° C. The drying can be carried out for any desired time periods from about 1 to about 20 hours.

The obtained diastereomeric salt of rivastigmine can be converted into rivastigmine free base by the use of base and solvent.

Suitable aqueous bases that can be used for desaltification include, but are not limited to, inorganic bases such as alkali metal hydroxides, alkali metal alkoxides, or alkali metal carbonates; organic bases such as pyridine, lutidine, triethylamine, DMAP, dicyclohexylamine, or diisopropylethylamine; or the like. In one embodiment the base is aqueous potassium carbonate.

Suitable organic solvents that may be used in the above desaltification step includes halogenated solvents such as dichloromethane, ethylene dichloride, or chloroform; esters such as ethyl acetate, n-propyl acetate, or isopropyl acetate; hydrocarbon solvents such as toluene, xylene, hexane, heptane, or cyclohexane; ethers such as 1,4-dioxane, tetrahydrofuran, diethyl ether, methyl isobutyl ether, or di isopropyl ether; or mixtures thereof in various proportions.

In another aspect, the present application provides a process for the preparation of (S)-rivastigmine or a pharmaceutically acceptable salt thereof, the process comprising the steps of:

a) reaction of 3-hydroxyacetophenone with N-ethyl-methyl carbamoyl chloride in the presence of a base to give ethyl-methyl-carbamic acid 3-acetyl-phenyl ester;

b) stereoselective reduction of 3-acetylphenyl ethyl (methyl) carbamate in presence of {(S)-Xyl-Binap-RuCI2-(S)-Daipen a base and hydrogen gas pressure, to give (R)-3-(1 -hydroxyethyl)phenyl ethyl(methyl)carbamate;

c) reaction of (R)-3-(1-hydroxyethyl)phenyl-ethyl(methyl)carbamate with methanesulfonyl chloride in presence of a base to give (R)-1-(3-((ethyl(methyl)carbamoyloxy)phenyl)ethyl methanesulfonate followed by in situ reaction with dimethylamine to give (S)-rivastigmine,

d) the (S)-rivastigmine obtained in step (c) is resoluted using 'Dutch Resolution' to get pure (S)-rivastigmine, and

e) optionally converting the (S)-rivastigmine into pharmaceutically acceptable salt.

Step (a) involves reaction of 3-hydroxyacetophenone of formula VIII with N-ethyl-methyl carbamoyl chloride in the presence of a base to give ethyl-methyl-carbamic acid 3-acetyl-phenyl ester of formula VII.

Suitable bases that can be used in step a) include, but are not limited to, inorganic bases such as alkali metal hydrides, alkali metal hydroxides, alkali metal alkoxides, or alkali metal carbonates; organic bases such as pyridine, lutidine, triethylamine, DMAP, dicyclohexylamine, diisopropylethylamine, or the like. In one embodiment the base is potassium carbonate.

Suitable organic solvents that may be used in step a) include but are not limited to, ketonic solvent such as acetone, methyl isobutyl ketone, or methyl ethyl ketone; halogenated solvents such as dichloromethane, ethylene dichloride, or chloroform; esters such as ethyl acetate, n-propyl acetate, or isopropyl acetate; hydrocarbon solvents such as toluene, xylene, hexane., heptane, or cycloh.exane; ethers such as 1,4-dioxane or, tetrahydrofuran; or mixtures thereof in various proportions.
Suitable temperatures for conducting the reaction can range from about 15°C to about 100°C, in one embodiment from about 25°C to about 35°C. The reaction can be conducted till the completion of the reaction. Typically the reaction time varies from about 1 hour to about 10 hours.

The by-product, 1,3-diethyl-1,3-dimethyl urea, formed in this reaction step can be removed by an aqueous acidic wash after completion of the reaction.

Step (b) involves stereo selective reduction of 3-acetylphenyl ethyl (methyl) carbamate of formula VII in presence of {(S)-Xyl-Binap-RuCI2-(S)-Daipen, a base and hydrogen gas pressure to give (R)-3-(1-hydroxyethyl) phenyl ethyl (methyl) carbamate of formula VI.

Suitable organic solvents that may be used in step b) include alcohols such as methanol, ethanol, isopropyl alcohol, or 1-butanol; ketones such as acetone, methyl isobutyl ketone, or methyl ethyl ketone; halogenated solvents such as dichloromethane, ethylene dichloride, or chloroform; esters such as ethyl acetate, n-propyl acetate, or isopropyl acetate; hydrocarbon solvents such as toluene, xylene, hexane, heptane, or cyclohexane; ethers such as 1,4-dioxane or tetrahydrofuran; or mixtures thereof in various proportions
Suitable hydrogen pressures that may be used in step b) are about 1 kg/cm2 to about 10 kg/cm2 pressure. Suitable temperatures for conducting hydrogenation reaction can range from about 15°C to about 100°C, in one embodiment from about 25°C to about 35°C. The reaction can be conducted till the completion of the reaction. Typically the reaction time varies from about 1 hour to about 30 hours.

The by-product 3-(1-hydroxyethyl)phenol formed in this reaction step can be removed by washing the reaction mass with basic water washing. In one embodiment 10% aqueous potassium carbonate solution is used to afford product of 98% purity.

Step (c) involves reaction of (R)-3-(1-hydroxyethyl) phenylethyl (methyl) carbamate of formula VI with methane sulfonyl chloride in presence of a base and solvent to give (R)-1-(3-((ethyl (methyl) carbamoyloxy) phenyl) ethyl methanesulfonate of formula V followed by in situ reaction with dimethylamine to give (S)-rivastigmine.

Suitable bases that can be used in the reaction of (R)-3-(1-hydroxyethyl)phenyl ethyl(methyl)carbamate with methanesulfonyl chloride include organic bases such as pyridine, lutidine, triethylamine, DMAP, dicyclohexylamine, diisopropylethylamine, or the like. In one embodiment the base is triethylamine. The suitable organic solvents that may be used in this reaction includes hydrocarbon solvents such as toluene, xylene, hexane, heptane, or cyclohexane; ethers such as 1, 4-dioxane or tetrahydrofuran; or mixtures thereof in various proportions.

Suitable temperature that may be used for the addition of sulfonyl chloride can range from about -10°C to about 50°C, in one embodiment from about 0°C to about 15°C. The reaction can be conducted till the completion of the reaction. Typically the reaction time varies from about 1 hour to about 5 hours.

After completion of the reaction the obtained (R)-1-(3-((ethyl(methyl) carbamoyloxy)phenyl)ethylmethanesulfonate may be optionally isolated or further reacted in situ with dimethylamine solution (20%) in a solvent to get (S)-rivastigmine.
Suitable organic solvents that may be used in this reaction includes hydrocarbon solvents such as toluene, xylene, hexane, heptane, or cyclohexane; ethers such as 1,4-dioxane or tetrahydrofuran; or mixtures thereof in various proportions. Suitable temperatures for conducting the reaction can range from about 0°C to about reflux temperature, in one embodiment from about 20°C to about 30°C.

Step (d) involves 'Dutch Resolution' of the (S)-rivastigmine obtained in step (C). The process of Dutch resolution comprises preparation of a solution of chirally impure (S)-rivastigmine followed by treatment with mixture of chiral resolving agents in the presence of a suitable solvent at suitable temperatures to form diastereomeric salt.
Solution of (S)-rivastigmine can be prepared by dissolving (S)-rivastigmine prepared using any of the processes known in the art.

Suitable mixture of chiral resolving agents which can be used for the process include, but are not limited to chiral agents such as di-O-p-toluoyl-D-tartaric acid, tartaric acid, camphorsulfonic acid, bromocamphorsulfonic acid, or the like.

Suitable mole ratio of mixture of chiral acids used for the Dutch resolution of can range from about 1:0.25, and in one embodiment about 1:0.5 equivalent.

Suitable organic solvents for formation of diastereomeric salt of rivastigmine include alcohols such as methanol, ethanol, isopropyl alcohol, or 1-butanol; ketones such as acetone, methyl isobutyl ketone, or methyl ethyl ketone; halogenated solvents such as dichloromethane, ethylene dichloride, or chloroform; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, t-butyl acetate, or the like; nitrile solvents such as acetonitrile, propionitrile or the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N,N-dimethylacetamide (DMA) or the like; or mixtures thereof in combination with water in various proportions.

In one embodiment suitable solvents that were used in Dutch resolution can be mixture of isopropyl alcohol and water and the ratio is 1:1.
The chiral resolving agent can be added to the solution of chirally impure (S)-rivastigmine at temperatures ranging from about 20°C to about 120°C or about 60°C to about 70°C.

After the addition of the chiral reagent, typically, for the product isolation to occur, the reaction mass may be maintained further at temperatures lower than the reaction temperatures such as for example below about 10°C to about 35°C, for a period of time as required for a more complete isolation of the product. A person skilled in the art can readily determine the exact cooling temperature and time required for complete isolation.

The diastereomeric salt of rivastigmine is isolated from the final mixture by any of the techniques such as filtration by gravity, or by suction, centrifugation, and the like. The crystals so isolated will carry a small proportion of occluded mother liquor containing a higher percentage of impurities. If desired, the crystals can be washed on the filter with a solvent to wash out the mother liquor.

The wet cake obtained in this step may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or the like. The drying can be carried out at temperatures of about 35° C to about 70° C. The drying can be carried out for any desired time periods from about 1 to about 20 hours.

The obtained diastereomeric salt of rivastigmine can be converted into pure (S)-rivastigmine free base by the use of base and solvent.

The pure (S)-rivastigmine free base so obtained is converted to its pharmaceutical^ acceptable salt.

In one aspect, the pharmaceutically acceptable salt of rivastigmine is rivastigmine hydrogen tartrate.

In another aspect, the present application provides a process for purification of rivastigmine comprising,

a) treating the crude rivastigmine with a suitable resin in presence of a solvent, and

b) isolating the pure rivastigmine form the mixture.

The rivastigmine obtained by the processes described above can be purified by treating with resin to afford the pure rivastigmine. Suitable resins that may be used to purify rivastigmine include polystyrene-based sulfonic acid catalysts. In one aspect the sulfonic acid catalysts may sulfonated polystyrene resins (which typically differ in the overall number of sulfonic acid groups on the resin), including Tulsion T 20 H, Indion, Amberlyst® XN-1010, Amberlyst® 15, Amberjet 1200H, Amberlite IR 400, Lewalit 2649, Dowex, Amberlite IR 120, Amberlite®, XE586®, Indion 140 or the like; sulfonated polyfluorocarbon resins, including Nafion-H.® resin; Oxycellulose; SP Trisacryl ®; other resins, such as, for example, SP Trisacryl Plus M® or SP Trisacryl Plus LS.®; poly (N-tris[hydroxymethyl]methyl methacrylamide resin; or the like.
The cation exchange resins may be readily separated from the overall reaction mixture by any means including but not limited to filtration, and any recovered resins may be re-used. Filtration may be achieved by any means including the use of Whatman paper, 100 mesh screens, 5-20 micron filter cartridges, or the like.
(1S, 1'R)-1, 1'-(oxybis (3, 1-phenylene)) bis (N, N-dimethylethanamine) (Impurity H) is the impurity formed during this reaction and this impurity can be removed by treating with resin.

In yet another aspect, the present application provides rivastigmine free base or its pharmaceutically acceptable salt thereof which is substantially free of related impurities, such as, for example, process, structural, or isomeric impurities.

"Substantially free of related impurities" means that rivastigmine free base or its pharmaceutically acceptable salts may be at least about 98%, or at least about 99.5%, or at least about 99.9% pure, and, correspondingly, the level of impurities may be less than about 2%, or less than about 0.5%, or less than about 0.1%, by weight as determined by gas chromatography or high performance liquid chromatography.

In an aspect, this application provides rivastigmine free base or its pharmaceutically acceptable salts, prepared by the processes herein described above, having each one or none of the following impurities, at amount determined by gas chromatography or high performance liquid chromatography, namely:

Impurity A: 3-vinylphenyl ethyl(methyl) carbamate

Impurity B: 3-(1-(dimethylamino)ethyl) phenyl dimethylcarbamate

Impurity C: 3-(1-chloroethyl)phenyl ethyl (methyl)carbamate

Impurity D: 1-(3-(benzyloxy)phenyl)-N,N-dimethylethanamine

Impurity E: (S)-3-(1-(dimethylamino)ethyl) phenyl methanesulfonate

Impurity F: 3-acetylphenylethyl (methyl) carbamate

Impurity G: 3-[(2-ethylmethylcarbamyl)ethyl]phenylethyl (methyl) carbamate

Impurity H: (1S, 1'R)-1, 1'-(oxybis (3, 1-phenylene)) bis (N, N-dimethylethanamine)

Impurity I: (R)-3-(1-hydroxyethyl) phenyl ethyl (methyl) carbamate ((R)-rivastigmine)

Impurity I

In an aspect, this application provides rivastigmine or its pharmaceutically acceptable salts, prepared by the processes herein described above, having any or each one the above described impurities in an amount less than about 0.15%.

In an aspect, this application provides rivastigmine or its pharmaceutically acceptable salts, prepared by the processes herein described above, having a purity as measured by gas chromatography or high performance liquid chromatography of at least about 98%, more preferably, at least about 99% and most preferably at least about 99.5%.
Preferably the chemical purity of the rivastigmine or its pharmaceutically acceptable salt is about 99% or more, more preferably about 99.5% or more, most preferably about 99.8% or more as measured by gas chromatography or high performance liquid chromatography.

In an aspect, this application provides rivastigmine free base or its pharmaceutically acceptable salts, prepared by the processes herein described above, substantially free of residual solvent.

"Substantially free of residual solvent" means that the amount of residual solvent is at least within the limits as specified by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines. For example, rivastigmine freebase may have an amount of residual ethanol less than limit of quantification (ICH limit: 5000 ppm); residual acetone less than limit of quantification (ICH limit: 5000ppm); and residual isopropanol is not detected (ICH limit: 5000 ppm), residual dichloromethane less than limit of quantification (ICH limit: 600 ppm), residual toluene less than 74 (ICH limit 890), residual ethyl acetate less than 2697 (ICH limit 5000).

Aspects of the present application also relate to pharmaceutical compositions comprising rivastigmine or a salt thereof, obtained by a process described in this application.
Pharmaceutical compositions comprising rivastigmine or a salt thereof, and their combinations with pharmaceutically acceptable excipients may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; and liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions. Formulations may be in the form of immediate release, delayed release, or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using process steps such as direct blending, dry granulation, wet granulation, or by extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Compositions of the present invention may further comprise one or more pharmaceutically acceptable excipients.

Pharmaceutically acceptable excipients that are useful for preparing formulations include, but are not limited to, any one or more of: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidones, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcellulosess, ethyl celluloses, methyl celluloses, various grades of methyl methacrylates, waxes, and the like. Other pharmaceutically acceptable excipients that are useful include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.

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 ETHYL-METHYL-CARBAMIC ACID -3-ACETYL PHENYL ESTER (FORMULA VII)

To a solution of 3-hydroxyacetophenone (59.15 g) (Formula VIII) in acetone( 500 mL), potassium carbonate (142.6 g) was charged and stirred for about 10 minutes. To the above reaction mixture N- ethyl-methyl carbamoyl chloride (50 g) was added over about 60 minutes followed by heating to about 55°C and stirred for about 6 hours. After completion of the reaction, the reaction was cooled to 50°C, filtered, and the collected solid washed with acetone (2x 100 mL). The obtained filtrate was evaporated completely under vacuum to afford the residue. The obtained residue was dissolved in dichloromethane (500 mL), the organic layer washed with 50% aqueous hydrochloric acid followed by washing with 0.5%(N) sodium hydroxide solution (2X100 mL) and with water (2x100 mL). To the obtained clear solution, activated carbon (2.5 g) was added, heated to about 40°C, stirred for about 60 minutes, and filtered through Celite. The Celite was washed with dichloromethane (100 mL). The obtained clear combined solution was evaporated completely under vacuum to afford the 83 g of the title compound as yellow oily syrup. GC purity: 99.09%

EXAMPLE 2: PREPARATION OF ETHYL-METHYL-CARBAMIC ACID -3-ACETYL PHENYL ESTER (FORMULA VII)

To a solution of 3-hydroxyacetophenone (88.7 g) (Formula VIII) in acetone( 750 mL), potassium carbonate (213.9 g) was charged and stirred for about 10 minutes. To the above reaction mixture N- ethyl-methyl carbamoyl chloride (75 g) was added over about 60 minutes followed by heating to about 55°C and stirred for about 6 hours. After completion of the reaction, the reaction was cooled to 50°C, filtered, and the collected solid washed with acetone (2x 150 mL). The obtained filtrate was evaporated completely under vacuum to afford the residue. Ttie obtained residue was dissolved in dichloromethane (750 mL), the organic layer washed with 50% aqueous hydrochloric acid followed by washing with 0.5%(N) sodium hydroxide solution (2X150 mL) and with water (2x150 mL). To the obtained clear solution, activated carbon (4.0 g) was added, heated to about 40°C, stirred for about 60 minutes, and filtered through Celite. The Celite was washed with dichloromethane (100 mL). The obtained clear combined solution was evaporated completely under vacuum to afford the 125 g of the title compound as yellow oily syrup. GC purity: 99.1%

EXAMPLE 3: PREPARATION OF (R)-3-(1-HYDROXYETHYL) PHENYL ETHYL(METHYL)CARBAMATE (FORMULA VI)

A solution of ethyl-methyl-carbamic acid 3-acetyl phenyl ester (100 mL) (Formula IV) in isopropyl alcohol (700 mL) was added into the autoclave and stirred for about 10 minutes. Then {(S)-Xyl-Binap-RuCI2-(S)-Daipen (55.2 mg) and a 1 M solution of potassium tert butoxide in THF (10 mL) was added into the reaction mixture, about 8 kg/cm2 of hydrogen gas is applied, and maintained for about eight hours at 30°C up to the completion of the reaction. After completion of the reaction the reaction solution was evaporated completely under vacuum at 60°C. Toluene (700 mL) was added to the obtained crude and the organic layer washed with water (1000 mL) and with 10 % aqueous K2C03 solution (500 mL). The separated organic layer was washed with brine solution, activated carbon (5 g) was added, heated to reflux, and stirred for about 30 minutes. The resulting reaction solution filtered through Celite and the Celite washed with toluene (100 mL). The obtained clear solution was concentrated under vacuum at 60°C to afford 89 g of the title compound. G.C. purity: 99.13% Chiral purity: (+)-99.55%

EXAMPLE 4: PREPARATION OF (R)-3-(1-HYDROXYETHYL) PHENYL ETHYL(METHYL)CARBAMATE (FORMULA VI)

A solution of ethyl-methyl-carbamic acid 3-acetyl phenyl ester (65 mL) (Formula IV) in isopropyl alcohol (450 mL) was added into the autoclave and stirred for about 10 minutes. Then {(S)-Xyl-Binap-RuCI2-(S)-Daipen (35.9 mg) and a 1 M solution of potassium tert butoxide in THF (6.5 mL) was added into the reaction mixture, about 7 kg/cm2 of hydrogen gas is applied, and maintained for about eight hours at 30°C up to the completion of the reaction. After completion of the reaction the reaction solution was evaporated completely under vacuum at 60°C. Toluene (450 mL) was added to the obtained crude and the organic layer washed with water (650 mL) and with 10 % aqueous K2C03 solution (350 mL). The separated organic layer was washed with brine solution, activated carbon (3.5 g) was added, heated to reflux, and stirred for about 30 minutes. The resulting reaction solution filtered through Celite and the Celite washed with toluene (60 mL). The obtained clear solution was concentrated under vacuum at 60°C to afford 59 g of the title compound. G.C. purity: 99.6% Chiral purity: (+)-99.55%

EXAMPLE 5: PREPARATION OF (S)-N-ETHYL-N-METHYL-3-n-(DIMETHYLAMINO) ETHYL1 PHENYL CARBAMATE ((S)-rivastiamine)

To a solution of (R)-3-(1-hydroxyethyl)phenylethyl(methyl)carbamate (100 g) (Formula VI) in toluene (600 mL), triethylamine ( 68 g) was added, stirred for about 15 minutes, and cooled to 0-5°C. Methanesulfonyl chloride (41.6 g) was added slowly through a dropper for about one hour at about 0°C and stirred up to completion of the reaction. After completion of the reaction, a mixture of dimethyl amine (604.6 g) and toluene was added slowly and stirred up to completion of the reaction. The obtained reaction solution was washed with water (500 mL), with brine solution (500 mL), and the organic layer separated and evaporated completely under vacuum to afford the title compound as oily mass.

The obtained oily crude was dissolved in toluene (250 mL). Indion 140 resin (activated by isopropyl alcohol (50 mL)) were added, stirred for about 5-6 hours at room temperature, and filtered. The obtained filtrate was evaporated completely under vacuum to obtain 68.25 g of the title compound. G.C. purity: 98.6%

EXAMPLE 6; PREPARA^ON~OF(S)-N-ETHYL-N-METHYL-3-[1-(DIMETHYLAMINO) ETHYLl PHENYL CARBAMATE ({SVrivastiamine)

To a solution of (R)-3-(1-hydroxyethyl)phenylethyl(methyl)carbamate (50 g) (Formula VI) in toluene (300 mL), triethylamine ( 34 g) was added, stirred for about 15 minutes, and cooled to 0-5°C. Methanesulfonyl chloride (21.5 g) was added slowly through a dropper for about one hour at about 0°C and stirred up to completion of the reaction. After completion of the reaction, a mixture of dimethyl amine (302.5 g) and toluene was added slowly and stirred up to completion of the reaction. The obtained reaction solution was washed with water (300 mL), with brine solution (300 mL), and the organic layer separated and evaporated completely under vacuum to afford the title compound as oily mass.

The obtained oily crude was dissolved in toluene (150 mL). Indion 140 resin (activated by isopropyl alcohol (30 mL)) were added, stirred for about 5-6 hours at room temperature, and filtered. The obtained filtrate was evaporated completely under vacuum to obtain 35.25 g of the title compound. G.C. purity: 98.3%

EXAMPLE 7: PREPARATION OF (S)-3-(1-(DIMETHYLAMINO)ETHYL)PHENYL ETHYL(METHYL)CARBAMATEf2R,3R)-2.3-BIS(4-METHYLBENZOYLOXY) SUCCINATE HYDRATE

A solution of (S)-3-(1-(dimethylamino)ethyl)phenyl(methyl)carbamate (25 g) ((S)-rivastigmine) in isopropyl alcohol (125 mL) and water (125 mL) was stirred for about 15 minutes. Di-O-p-toluoyl tartaric acid (40.4 g) and L(+)-tartaric acid (7.5 g) were added, heated to reflux, and maintained for about 60 minutes until clear solution was obtained. The resultant reaction solution was cooled to about 0°C to about 5°C and stirred for solid separation. The separated solid was collected by filtration, washed the solid with water (50 mL), and dried by suction under vacuum. The obtained wet cake was placed into a clean dry round bottom flask containing isopropyl alcohol (135 mL) and water (135 mL), stirred for about 15 minutes, heated to reflux to get clear solution, and maintained at that temperature for about one hour. The resulting clear solution was cooled to about 25-35°C, stirred for about 1 hour, further cooled to about 0-5°C, and stirred for about 1 hour. The separated solid was collected by filtration, washed with water (115 mL), and dried by suction. The obtained solid dried under vacuum to afford 39.8 g of the title compound. purity = 99.9% Chiral purity = 99.93%

EXAMPLE 8: PREPARATION OF (SV3-(1-(DIMETHYLAMINO)ETHYL)PHENYL ETHYL(METHYL)CARBAMATE(2R.3R)-2.3-BIS(4-METHYLBENZOYLOXY) SUCCINATE HYDRATE

A solution of (S)-3-(1-(dimethylamino)ethyl)phenyl(methyl)carbamate (50 g) ((S)-rivastigmine) in isopropyl alcohol (250 mL) and water (250 mL) was stirred for about 15 minutes. Di-O-p-toluoyl tartaric acid (80.0 g) and L(+)-tartaric acid (15 g) were added, heated to reflux, and maintained for about 60 minutes until clear solution was obtained.

The resultant reaction solution was cooled to about 0°C to about 5°C and stirred for solid separation. The separated solid was collected by filtration, washed the solid with water (100 mL), and dried by suction under vacuum. The obtained wet cake was placed into a clean dry round bottom flask containing isopropyl alcohol (250 mL) and water (250 mL), stirred for about 15 minutes, heated to reflux to get clear solution, and maintained at that temperature for about one hour. The resulting clear solution was cooled to about 25-35°C, stirred for about 1 hour, further cooled to about 0-5°C, and stirred for about 1 hour.

The separated solid was collected by filtration, washed with water (230 mL), and dried by suction. The obtained solid dried under vacuum to afford 80 g of the title compound, purity = 99.89% Chiral purity = 99.94%

EXAMPLE 9: PRPEARATION OF (S)-RIVASTIGMINE (S)-3-(1-(dimethylamino)ethyl)phenyl ethyl(methyl)carbamate(2R,3R)-2I3-bis(4-
methylbenzoyloxy)succinate Hydrate (84 g) was added into a clean dry round bottom flask containing 10% aqueous potassium carbonate solution (420 mL) and stirred for about 30 minutes. To the reaction solution, ethyl acetate (420 mL) was added and stirred for about 30 minutes. The organic and aqueous layers were separated. To the aqueous layer ethyl acetate (2x210 mL) was added and separated the organic layer. The organic layer was combined and washed with water and dried over sodium sulphate and distilled off completely to obtain 29.5 g of the title compound as oily liquid. GC purity: 99.80% Chiral purity: 99.97% Impurity content by GC: 3-Hydroxyacetophenone: Not detected 3-vinylphenyl ethyl(methyl) carbamate (Impurity A): 0.02% 3-(1-(dimethylamino)ethyl) phenyl dimethylcarbamate (Impurity B): Not detected 1-(3-(benzyloxy)phenyl)-N,N-dimethylethanamine (Impurity D): 0.03% (S)-3-(1-(dimethylamino)ethyl) phenyl methanesulfonate (Impurity E): Not detected 3-acetylphenylethyl (methyl) carbamate (Impurity F): 0.08%3-[(2-ethylmethylcarbamyl)ethyl]phenylethyl (methyl) carbamate (Impurity G): Not detected Impurity content by HPLC: 3-(1-chloroethyl)phenyl ethyl (methyl)carbamate (Impurity C): Not detected (1S, 1'R)-1, 1'-(oxybis (3, 1-phenylene)) bis (N,N-dimethylethanamine) (Impurity H): Not detected (R)-3-(1-hydroxyethyl) phenyl ethyl (methyl) carbamate ((R)-rivastigmine) (Impurity I): .03%

EXAMPLE 10: PRPEARATIQN OF (S)-RIVASTIGMINE

(S)-3-(1-(dimethylamino)ethyl)phenyl ethyl(methyl)carbamate(2R,3R)-2,3-bis(4-
methylbenzoyloxy)succinate Hydrate (140 g) was added into a clean dry round bottom flask containing 10% aqueous potassium carbonate solution (700 mL) and stirred for about 30 minutes. To the reaction solution, ethyl acetate (700 mL) was added and stirred for about 30 minutes. The organic and aqueous layers were separated. To the aqueous layer ethyl acetate (2x350 mL) was added and separated the organic layer. The organic layer was combined and washed with water and dried over sodium sulphate and distilled off completely to obtain 50 g of the title compound as oily liquid. GC purity: 99.82% Chiral purity: 99.92

EXAMPLE 11: PREPARATION OF S)-3-(1-(DIMETHYLAMINO)ETHYL)PHENYL ETHYL(METHYL)CARBAMATE(2R.3R)-2.3-BIS(4-ETHYLBENZOYLOXY) SUCCINATE HYDRATE USING RACEMIC RIVASTIGEMINE BY USING DUTCH RESOLUTION

Racemic rivastigmine (25 g) was added into a clean dry round bottom flask containing mixture of isopropyl alcohol (125 mL) and water (125 mL) and stirred for about 10 minutes. To the obtained reaction solution, a mixture of Di-O-p-toluoyl tartaric acid (40.3 g) and L(+)-tartaric acid (7.48 g) was added, heated to about 90°C, maintained at this temperature for about one hour, cooled to 35°C, and stirred for solid separation. The separated solid was collected by filtration, washed with water, and dried under vacuum for about two hours at 70°C. The obtained solid was charged into a clean dry round bottom flask containing isopropyl alcohol (100 mL) and water (100 mL), heated to about reflux, and maintained for about one hour. The resultant reaction solution was cooled to 0-5°C and stirred for solid separation. The separated solid was collected by filtration and washed with water and dried under vacuum for two hours at 70°C to afford (S)-3-(1-(dimethylamino)ethyl)phenylethyl(methyl)carbamate(2R,3R)-2,3-bis(4-methylbenzoyloxy) succinate hydrate. The obtained title compound can be optionally purified by the repeated recrystallization using the mixture of isopropyl alcohol and water.

EXAMPLE 12: PREPARATION OF S)-3-(1-(DIMETHYLAMINO)ETHYL)PHENYL ETHYL(METHYL)CARBAMATE(2R.3RV2.3-BIS(4-ETHYLBENZOYLOXY) SUCCINATE HYDRATE USING RACEMIC RIVASTIGEMINE BY USING DUTCH RESOLUTION

Racemic rivastigmine 100 g) was added into a clean dry round bottom flask containing
mixture of isopropyl alcohol (500 mL) and water (500 mL) and stirred for about 10 minutes.

To the obtained reaction solution, a mixture of Di-O-p-toluoyl tartaric acid (161 g) and L(+)-tartaric acid (30 g) was added, heated to about 90°C, maintained at this temperature for about one hour, cooled to 35°C, and stirred for solid separation. The separated solid was collected by filtration, washed with water, and dried under vacuum for about two hours at 70°C. The obtained solid was charged into a clean dry round bottom flask containing isopropyl alcohol (400 mL) and water (400 mL), heated to about reflux, and maintained for about one hour. The resultant reaction solution was cooled to 0-5°C and stirred for solid separation. The separated solid was collected by filtration and washed with water and dried under vacuum for two hours at 70°C to afford (S)-3-(1- (dimethylamino)ethyl)phenylethyl(methyl)carbamate(2R,3R)-2,3-bis(4-methylbenzoyloxy) succinate hydrate. The obtained title compound can be optionally purified by the repeated recrystallization using the mixture of isopropyl alcohol and water.

EXAMPLE 13; Gas Chromatography method for rivastigmine and impurities

Chromatographic Conditions:

Column: Agilent 6890N GC System with an auto sampler or equivalent
Length: 30 meters
ID: 0.53 mm
Film thickness: 1.0 microns
Column Temperature: Initial temperature: 150°C, Hold time: 5 minutes, Heating rate: 15°C,
Final temperature: 220°C, Final hold time: 80 minutes
Injection port temperature: 220°C
Detector temperature: 250°C
Carrier gas: Helium
Flow rate: 4.0mL/ min

Split ratio: 7:1 Injection volume: 2.Out-Run time: 90 minutes Diluent: Toluene
PEAK LOCATIONS:
EXAMPLE 14; High Performance Liquid Chromatography (HPLC) method for rivastiamine
and impurities
Chromatographic Conditions:
Column: XTerra RP-18, 250 x 4.6 mm, 5.0 p particle size.
Column Temperature: 25°C ± 2°C.
Mobile phase: Mobile phase A: Dissolved 0.5mL of Trifluro acetic acid in 1000mL of MQ
water, then mixed well, degassed and filtered.
Mobile phase B: Mixed 0.5mL of Trifluro acetic acid in 1000mL of HPLC grade Acetonitrile
then mixed well, degassed and filtered.

Diluent: Water: Acetonitrile:: 50:50 (v/v) Flow Rate: 1 .OmL per minute Wavelength of detection: 217 nm Injection Volume: 50uL

CLAIMS We claim

1. A process for the optical resolution of racemic or enantiomerically enriched rivastigmine comprising crystallization of racemic or enantiomerically enriched rivastigmine with a mixture of chiral resolving agents.

2. The process according to claim 1, wherein the chiral resolving agent is selected form di-O-p-toluoyl-D-tartaric acid, tartaric acid, citric acid, camphorsulfonic acid, bromo camphorsulfonic acid.

3. A process for the preparation of (S)-rivastigmine or a pharmaceutically acceptable salt thereof, the process comprising the steps of:

a), reaction of 3-hydroxyacetophenone of formula VIII with N-ethyl-methyl carbamoyl chloride in the presence of a base to give ethyl-methyl-carbamic acid 3-acetyl-phenyl ester of formula VII
Formula VIII Formula VII

b). stereoselective reduction of 3-acetylphenyl ethyl (methyl) carbamate of formula VII in presence of {(S)-Xyl-Binap-RuCI2-(S)-Daipen, base and hydrogen gas pressure to give (R)-3-(1-hydroxyethyl)phenyl ethyl(methyl)carbamate of formula VI

Formula VII DAIPEN] Formula VI

c). reaction of (R)-3-(1-hydroxyethyl)phenyl-ethyl(methyl)carbamate of formula VI with methanesulfonyl chloride in presence of a base to give (R)-1-(3-((ethyl(methyl)carbamoyloxy)phenyl)ethyl methanesulfonate of formula V followed by in situ reaction with dimethylamine to give (S)-rivastigmine

d) the (S)-rivastigmine obtained in step (c) is resoluted using 'Dutch Resolution' to
get pure (S)-rivastigmine, and e). optionally converting the (S)-rivastigmine into pharmaceutically acceptable salt.

4. The process according to claim 3, wherein the base used in step (b) is selected from the group consisting of sodium tertiary butoxide, potassium tertiary butoxide, sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.

5. The process according to claim 4, wherein the base is potassium tertiary butoxide.

6. A process for purification of rivastigmine comprising:

a) treating the crude rivastigmine with a suitable resin in presence of a solvent, and

b) isolating the pure rivastigmine form the mixture.

7. The process according to claim 6, wherein the resin is selected from the group consisting of Tulsion T 20 H, Indion, Amberlyst® XN-1010, Amberlyst® 15, Amberjet 1200H, Amberlite IR 400, Lewalit 2649, Dowex, Amberlite IR 120, Amberlite®, XE586®, Indion 140.

8. The process according to claim 7, wherein the resin is Indion 140.

9. The process according to claim 6, wherein the solvent is a mixture of toluene and isopropyl alcohol.

10. A process for reduction of 3-acetylphenyl ethyl (methyl) carbamate of formula VII in presence of {(S)-Xyl-Binap-RuCI2-(S)-Daipen, base and hydrogen to give (R)-3-(1- hydroxyethyl)phenyl ethyl(methyl)carbamate of formula VI