FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule I3)
"PROCESSES FOR THE PREPARATION OF PROPARGYLATED AMINOINDANS OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF"
Glenmark Generics Limited an Indian Company, registered under the Indian company's Act 1957 and having its
registered office at
Glenmark House.
HDO - Corporate Bldg. Wing-A
B.D. Sawant Marg. Chakala
Andheri (East), Mumbai - 400 099
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to processes for the preparation of propargylated aminoindans or their pharmaceutically acceptable salts and pharmaceutical compositions of the same.
BACKGROUND OF THE INVENTION 1. Technical Field
The present invention relates to processes for the preparation of propargylated aminoindans. compounds of formula I or their pharmaceutically acceptable salts and pharmaceutical compositions thereof.


wherein R1 = H or

2. Description of the Related Art
Rasagiline mesylate is an irreversible inhibitor of monoamine oxidase approved for the treatment of idiopathic Parkinson's disease. Rasagiline mesylate is chemically described as 5-N-propargyl-l -(R)-aminoindan mesylate and is represented by the structural formula


United.States Patent No. 3.513,244 (the '244 patent) describes propargylated aminoindans including racemic rasagiline. The 244 patent discloses the preparation of racemic rasagiline by reacting 1-haloindan with propargylamine.
United States Patent No. 5,532,415 (the '415 patent) describes optically pure rasagiline and its pharmaceutical]}' acceptable salts thereof. The '415 patent discloses the preparation of optically pure rasagiline by reacting optically pure 1-aminoindan with propargyl bromide or chloride or propargyl sulfonate ester in the presence of a base and optionally in the presence of a solvent. The '415 patent also discloses that enantiomerically pure aminoindan derivatives can be prepared by the optical resolution of racemic mixtures using any conventional resolution method, like preparative chromatography on a chiral column.
United States Patent No. 7,375,249 describes a process for the preparation of optically pure propargyl aminoindans by using optically active ligands and catalysts.
One of the compounds disclosed in PCT patent publication WO98/27055 (the WO '055 publication) is (R)-6-(N-methyl-N-ethylcarbamoyloxy)-N'-propargyl-1-aminoindan, also known as (3R)-3-(prop-2-ynylamino)-2,3,-dihydro-lH-inden-5-yl-ethylmethylcarbamate. Salts thereof are also disclosed, including a 1/2 L-tartrate salt. This salt has been given the nonproprietary name ladostigil tartrate.
The WO'055 publication discloses methods for the preparation of indanylamine and aminotetralin derivatives using, for example, 3-amino-indan-5-ol or 6-methoxy-indan-l-ylamine, as starting materials, including the starting materials for the compounds thereof.
The aforementioned processes for the synthesis of propargylated aminoindans, like rasagiline. employ: chromatographic separation of enantiomers, toxic and flammable chemicals, such as propargyl halides and propargyl sulfonate esters, which are difficult to handle, and costly chiral ligands
The enumerated factors above, at the least, subsequently may translate to higher costs, environmentally unsound and commercially un-scalable processes.
Further, some of the said methods produce low yields of the target compounds, due to the formation of significant amount of undesirable by-products, like bisalkylated

aminoindans and remaining of unreacted starling materials as residue which needs additional steps for recovery and purification methods.
Thus, there is a need for reliable processes, which are suitable for industrial production, in high yields, of indanyiamine derivatives as intermediates, to prepare aminoindan derivatives and specifically compounds of Formula I.
The present invention provides robust, reproducible, cost effective processes for preparation of propargylated aminoindans. like rasagiline.
SUMMARY OF THE INVENTION
The present invention relates to processes for the preparation of propargyiated aminoindans or pharmaceutically acceptable salts thereof
In one aspect, the present invention relates to a process for the preparation of a compound of formula I


wherein R1 = H or comprising:

a) reacting an indanone derivative or a salt thereof of formula II with the
propargylamine or a salt thereof of formula III in the presence of a Lewis acid; and


b) subjecting the resultant reaction mixture to reduction.
In another aspect, the present invention provides rasagiline or a pharmaceutically acceptable salt thereof, obtained by the processes herein described, having bisalkylated aminoindan or its enantiomer of structural formula

and 1-indanol of structural formula

each in an amount not more than about 0.15 area percent, as measured by high performance liquid chromatography (HPLC).
In another aspect, the present invention provides rasagiline or a pharmaceutically acceptable salt thereof, obtained by the processes herein described, having bisalkylated aminoindan or its enantiomer of structural formula XII and 1-indanol of structural formula XIII. in an amount not more than about 0.1 area %, as measured by HPLC.
In yet another aspect, the present invention relates to pharmaceutical compositions comprising propargylated aminoindans or their pharmaceutically acceptable salts thereof of formula I, obtained by the processes of present invention, and at least one pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE FIGURES
Fig. 1: is a Particle size distribution histogram according to Example 4
Fig 2 : is an X-ray powder diffractogram of rasagiiine mesylate according to Example 4.
RETAILED DESCRIPTION OT THE INVENTION
The present invention relates to processes for the preparation of propargylated aminoindans and pharmaceutically acceptable salts thereof.
In one embodiment, the present invention relates to a process for the preparation of a compound of formula I

wherein R1 - H or
comprising;
a) reacting an indanone derivative or a salt thereof of formula II with the propargylamine or
a salt thereof of formula III in the presence of a Lewis acid,

b) subjecting the resultant reaction mixture to reduction.
The reaction of the indanone of formula II and propargylamine of formula III is carried out in the presence of a Lewis acid to form the compound of formula IV wherein M represents its metal moiety and R4 represents the residue of a Lewis acid,


Lewis acid is an electrophilic compound, that can accept a pair of electrons from an electron-pair donor, forming an adduct by the formation of a coordinate covalent bond.
There is likewise no particular restriction on the nature of the Lewis acids used, and any Lewis acid commonly used in reactions of this type may equally be used here. Examples of Lewis acid include, but are not limited to: Ti-(TV)isopropoxide, aluminium isopropoxide, Aluminum ethoxide, Aluminum sec-butoxide. Aluminum tert-butoxide, Lithium isopropoxide, boron trifluoride (BF3), boron trifluoride etherate (BF3-OEt2). boron trichloride (BCl3), aluminium trichloride (AlCl3), zinc chloride (ZnCl2), Ferric chloride (FeCl3), magnesium chloride (MgCl2), antimony pentachloride (SbCL), silver chloride (AgCl), Ferric nitrate (Fe(N03)3), Triisopropylsilyl trifluoromethanesulfonate (CF3S03Si(CH3)3), Ytterbium trifluoromethanesulfonate (Yb(CF3S03)3) and Stannic chloride (SnCU) trimethylaluminum or triethylaluminum in toluene. Scandium triflate (Sc(OTf)3) Lanthanide trifluoromethanesulfonates (LafOTfk). Europium triflate (Eu(OTf)3), Copper(II) triflate (Cu(OTf)2), Zinc triflate (Zn(OTf)2) Titanium(III) chloride-aluminum chloride (AICI12T13 ), Titanium(IV)chloride, Titanium(IV)chloride tetrahydrofuran complex, Tin(IV) chloride (SnCU), Tin(IV) chloride pentahydrate (Cl4Sn 5H20 ), Boron trichloride methyl sulfide complex, Boron trifluoride acetic acid complex, Boron trifluoride phenol complex. Boron trifluoride phosphoric acid complex, Dicyclohexylboron trifluoromethanesulfonate, Iron(IIl) bromide, Iron(III) chloride hexahydrate. Aluminum bromide, Aluminum chloride THF complex, Montmorillonite (Aluminum Pillared Clay). Preferably, the Lewis acid is Ti-(IV) isopropoxide.
The reaction can be carried out in any suitable solvent or combination of solvents, for example, alcohols, such as methanol, ethanol, isopropyl alcohol, tertiary butyl alcohol and the like; halogenated solvents such as dichloromethane, ethylene dichloride. chloroform and

the like; hydrocarbons such as toluene, cyclohexane and the like: esters, such as ethyl acetate. n-propyl acetate, isopropyl acetate, tertiary butyl acetate and the like: ethers, such as tetrahydrofuran,l,4-dioxane. diisopropyl ether and the like: aprotic polar solvents, such as dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide and the like and mixtures thereof. Preferably, the solvent is ethanol or methanol.
The reaction can be carried out at any suitable temperature that allows for facile formation of Lewis acid complex, represented by a compound of formula IV.
Preferably the reaction is carried out at temperatures from at least about 25°C to at least about 35°C, more preferably from about at least 25°C to about at least 30°C.
The molar equivalents of Lewis acids used based on the weight of the indanone compound of formula II is from about 1: 1 to about 5: 1. Preferably the ratio is 1.2:1.
The molar equivalents of propargyl amine compound of formula HI used based on the weight of the indanone compound of formula II is from about 0.5: 1 to about 2:1. Preferably the ratio is 1:1.
In various embodiments, "alkyl" includes linear alkyls. branched alkyls, and cycloalkyls. Additionally, the alkyls may be substituted with alkoxy, halo, and like substitutents. In some embodiments, alkyl is a C1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, iso-butyl. sec-butyl, tert-butyl: cycloalkyl such as cyclopropyl, cyclobutyl, and the like.
In one embodiment, the present invention relates to a process for the preparation of a compound of formula I


wherein R1 = H or comprising:

a) reacting an indanone derivative or a salt thereof of formula II with the propargyl amine or a salt thereof of formula III in the presence of a Lewis acid of formula M-(R4)n (where n=Ito 5) to form a complex of formula IV

. wherein M represents its metal moiety and R4 represents the residue of a Lewis acid, b) subjecting the resultant reaction mixture to reduction. The schematic representation is as below

In one embodiment, the present invention presents a complex of formula IV. whereupon subjecting thereto said complex to reduction in the presence of an optically inactive reducing agent to form the compound of formula V,


wherein R1 is as defined above for formula I. and resolving the compound of formula V with a chiral resolving agent to form the compound of formula I.
The optically inactive reducing agent that can be used is selected from the group consisting of metal hydrides like sodium borohydride, aluminium hydride, lithium aluminium hydride, sodium cyanoborohydride or mixtures thereof. Preferably, the optically inactive reducing agent is sodium borohydride.
The solvent that can be used include, but are not limited to alcohols, such as methanol, ethanol, isopropyl alcohol, tertiary butyl alcohol and the like; halogenated solvents, such as dichloromethane, ethylene dichloride, chloroform and the like; hydrocarbons, such as toluene,, cyclohexane and the like; esters, such as ethyl acetate, n-propy! acetate, isopropyl acetate, tertiary butyl acetate and the like; ethers, such as tetrahydrofuran,l,4-dioxane, diisopropyl ether and the like; aprotic polar solvents, such as dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide and the like and mixtures thereof. Preferably, the solvent is methanol or ethanol.
The chiral resolving agent is selected from the group consisting of S-(+) mandelic acid, R-(-) mandelic acid. L-(+)tartaric acid, D-(-)tartaric acid, (-)-Dibenzoyl-L-tartaric acid, (-)-Dibenzoyl-L-tartaric acid monohydrate, (+)-Dibenzoyl-D -tartaric acid, (+)-Dibenzoyl-D -tartaric acid monohydrate, (+)-Dipara-toluoyl-D-tartaric acid. (+)-Dipara-toluoyl-D-tartaric acid monohydrate, (-)-Dipara-toluoyl-D-tartaric acid, (-)-Dipara-toluoyl—D-tartaric acid monohydrate, (lR)-(-)-10-camphorsulfonic acid, and (lS)-(+)-10-camphorsulfonic acid or mixtures thereof. Preferably the chiral acid used is L-(+) tartaric acid.
The reactions are carried out at temperatures from about at least 25°C to about at least 100°C. Preferably, from about 80°C to about 85QC.

The time period for th& reaction to complete can range from about at least 30 minutes to about at least 5 hours. Preferably, from about at least 30 minutes to about at least 1 hour.
The reactions can be carried out in the presence or absence of base and solvents.
The propagylated aminoindan complex formed in the preparation of rasagiline using the processes described above is represented by the formula VI

In another aspect, the present invention presents a process for the preparation of propargylated aminoindans of formula I comprising reduction of complex of formula IV

in the presence of optically active reducing agents or chiral ligands to form the compound of
formula I.
The optically active reducing agents that can be used include, but are not limited to L-selectride, 2,2'-dihydroxy-l,1-binaphthyl-lithium aluminum hydride (BINAL-H), Diisobutylaluminium hydride (DIBAL). (+)-B-Chlorodiiso-2-ethylapopinocampheylborane, . (+)-B-Fluorodiiso-2-ethylapopinocarnpheylbGrane, (+)-B-Bromodiiso-2-ethylapopino-campheyl-borane, bis(10-methylisopinocampheyl)chloroborane and the like or mixtures thereof. Preferably, L-selectride.
The chiral ligands that can be used is selected from the group consisting of [(R) HexaPHEMP RuCl2 (R,R)-DACH], [(R)-HexaPHEMP RuCl2 (R,R)-DPEN], [(R)-PhanePhos RuCl2 (S,S)-DACH], [(S)-PhanePhos RuCl2 (R,R)-DPEN], [(S)-MeO-Xylyl-PhanePhos RuCl2 (R,R)-DPEN], [(R)-MeO-Xylyl-PhanePhos RuCl2 (S.S)-DACH], [(S)-SynPhos RuCl2 (S,S)-

DPEN], [(S)-Xylyl-BINAP RuCl2 (SSS)-DPEN]S [(S)-F-Phenyl-PhanePhos RuCl2 (R,R)-DPEN], [(S)-MeO-Phenyl-PhanePhos RuCl2 (R,R)-DPEN], [(s)-MeO-Phenyl-PhanePhos RuCl2 (R,R)-DACH], [(R,R)-Me-DuPhos RuCl2 (R,R)-DPEN], [(R)-BINAP RuCl2 (R)-DAIPEN], [(R,R)-Et-DuPhos RuCl2 (R,R)-DACH], [R,R-TsDPEN (Ru) (p-cymene) CI], and [S,S-TsDPEN (Ru) (p-cymene) CI]. Preferably [(R)-BINAP RuCl2 (R)-DAIPEN].
An optically active reducing agent or chiral Jigand is used to attain enantiomeric selectivity and to afford the desired enantiomer in higher yield and purity.
The molar equivalents of optically active reducing agents or chiral ligand relative to the weight of the complex of formula JV taken is from about 1: 1 to about 5: I. Preferably the ratio is 2:1.
The solvents that can be used include, but are not limited to alcohols, such as methanol, ethanol, isopropyl alcohol, tertiary butyl alcohol and the like; halogenated solvents, such as dichloromethane, ethylene dichloride, chloroform and the like; hydrocarbons , such as toluene, cyclohexane and the like; esters, such as ethyl acetate, n-propyl acetate, isopropyl acetate, tertiary butyl acetate and the like; ethers, such as tetrahydrofuran,1.4-dioxane, diisopropyl ether and the like; aprotic polar solvents, such as dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide and the like and mixtures thereof. Preferably, methanol or ethanol.
The reactions are carried out at temperatures from about -25°C to about 35°C. Preferably, from about 25°C to about 30°C.
The time period for the reaction to complete can range from about 30 minutes to about 5 hours. Preferably from about 30 minutes to 1 hour.
The term "optically pure", as used herein, is intended to mean optical purity over about 90%. preferably over 95%, and more preferably over 99%, expressed as the percent enantiomeric excess. The terms "resolve" and "resolution", as used herein, are intended to encompass the complete or partial separation of the two optical enantiomers.
The compounds of formula (II) and (III) may be prepared by processes known in the art.
Suitably, one or more sequential steps are carried out, without isolating intermediate compounds.

The processes of the present invention produce chiral indanylamine derivatives from readily available, pro-chiral starting materials.
In one embodiment, the present invention provides propargylated aminoindans of interest are rasagiline represented by the formula VIII, the process for preparing is depicted in the scheme below.

In one embodiment, the present invention provides ladostigil represented by formula IX or a pharmaceutically acceptable salt thereof.


In an embodiment, the R-isomer of formula VIII is commonly known as rasagiline, which is herein rasagiline or R-rasagiline.
The present invention provides the mother liquor obtained in resolution of compound of formula V to compound of formula I, for example, or the mother liquor from recrystallizations, when optionally carried out. are rich with (S)-rasagiline: whereupon said (S)-rasagiline present in one or more of these liquors, or the pooled liquors; may be converted into racemic rasagiline for reuse in a process according to the present invention substantially as herein before described.
Suitably, one or more mother liquors obtained from a process as described above, or from a pooled mother liquors, may be treated with a base to remove any residual chiral acid and to thereby afford the free base enriched in (S)-rasagiJine. The free base can then be converted to the racemate, typically by reflux in a suitable solvent for several hours, optionally in the presence of a suitable acid, as for example in hydrochloric acid (HC1) or a base, as for example, sodium hydroxide (NaOH). and the resultant racemate can then be recycled for use in a process according to the present invention substantially as herein before described.
The processes known for the synthesis of propargylated aminoindans, like rasagiline and ladostigil. typically involve chromatographic separation of enantiomers. the use of toxic chemicals and flammable materials, like propargyl halides and propargyl sulfonate esters, including the use of expensive chiral precatalysts and ligands. which may render the processes to be expensive, non-ecofriendly, thus making said processes unsuitable on a commercial scale.
Of additional concern in these methods, is the low conversion of starting compounds like aminoindan into the desired products resulting to the presence of significant amounts of unreacted starting compounds and augmented by significant formation of undesirable bisalkylated by-products as impurities. These said unreacted starting compounds and impurities may need additional purification steps to produce the final products with desired purities.
Said methods are exemplified below, comparatively with the processes of the present invention.

The comparative example signifies that there is a need for reliable processes, which are suitable for industrial production, to produce indanylamine derivatives in high yields as intermediates, to prepare aminoindan derivatives and specifically compounds of Formula I.
The processes of the present invention require a few steps, thus making the processes applicable on an industrial scale. The compounds produced by the processes of the current invention are suitable for use as pharmaceuticals, or as starting materials or as intermediates in the production of a variety of pharmaceuticals. Thus, the present invention provides processes which are not only simple without employing environmentally aggressive chemicals, but more significantly, provide the least formation of undesirable bisalkylated by-products, while concomitantly producing final products in high yield and purity of rasagiline or pharmaceutically salts thereof.
In one more aspect, the present invention provides that the crystalline diastereomeric salt can be filtered and the free base liberated by basifying the salt with a suitable basifying agent. Said agents include, but are not limited to ammonia, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or mixtures thereof. Preferably, potassium carbonate solution or ammonia. The mother liquid can be recovered after filtering and be further treated in order to recover the enantiomer which was not previously removed by precipitation. The treatment may comprise e.g. cooling the mother liquid and recovering the resulting crystalline diastereomeric salt.
Typically, the product obtained by the above described method contains about 90 wt% of the desired enantiomer of formula (I). The purity of the product can be increased to about 96 wt% by recrystallization using suitable solvents. Methanol is the preferred recrystallization solvent. For example, the product which is enriched in (-)enantiomer is recrystallized by adding the product to methanol solvent, refluxing the mixture and filtering precipitate. The filtrate is concentrated, if necessary, and cooled in order to crystallize the (R)-enantiomer of formula (I). This allows recovering the substantially pure (-) enantiomer of formula (I) from the mother solution by crystallization.
The precipitation is carried out with cooling, decreasing the amount of the solvent and/or by adding an antisolvent.
The free base obtained may be optionally purified by recrystallization or slurrying in suitable solvents.

Recrystallization involves providing a solution of crude R-rasagiline in a suitable solvent and then crystallizing the solid from the solution.
Suitable solvents in which R-rasagiiine can be dissolved for purification include, but are not limited to, C1-C5 ketones, such as acetone, ethyl methyl ketone, butanone and the like; alcohols, such as ethanol, methanol, and isopropanol; ethers, such as such as tetrahydrofuran, 1,4-dioxane, ethyl acetate and the like; water; and mixtures thereof. Preferably, the solvent is acetone or ethyl acetate.
The concentration of the R-rasagiline in a solvent or mixture of solvents can range from about 40% to greater than about 80%. The solution can be prepared at an elevated temperature if desired to achieve a higher solute concentration. Any temperature is acceptable for the dissolution as long as a clear solution of the R-rasagiline is obtained and is not detrimental to the drug substance chemically or physically. The solution may be brought down to a lower temperature for further processing if required or an elevated temperature may be used. A higher temperature for dissolution will allow the precipitation from solutions with higher concentrations of R-rasagiline.
The product may optionally be further dried. Drying can be suitably 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. The drying can be carried out for any desired time periods to achieve the desired product purity.
The process of the present invention may further comprise the conversion of a product into a pharmaceutically acceptable salt. In the practice of this invention, pharmaceutically acceptable salts include, but are not limited to, the mesylate, maleate, fumarate. tartrate, hydrochloride, hydrobromide, esylate. p-toluenesulfonate. benzoate. acetate, phosphate and sulfate salts. The present invention additionally comprises products as pharmaceutically acceptable salts. Preferably, mesylate or tartrate.
The present invention provides the process of preparing the pharmaceutically acceptable salt of R-rasagiline comprising reacting a pharmaceutically acceptable acid with R-rasagiline in solution.
Optionally, the acid is dissolved in a solvent before adding it to the solution of R-rasagiline free base.

The solvent used for the dissolution of R-rasagiline and the acid may be the same, or different solvents may be used.
Suitable solvents in which the acid addition salt of R-rasagiline can be prepared include, but are not limited to C1-C5 ketones, such as acetone, ethyl methyl ketone, butanone and the like; alcohols, such as ethanol. methanol, and isopropanol; ethers, such as tetrahydrofuran, 1.4-dioxane, ethyl acetate and the like water; and mixtures thereof.
In one preferred embodiment the mesylate of R-rasagiline is prepared from R -rasagiline and methanesulfonic acid in acetone.
In one embodiment the present invention provides a process for preparing R-rasagiline mesylate having a particle size distribution wherein 90% of particles (D90) have particle size greater than 1500μm, comprising reacting R -rasagiline with methanesulfonic acid in methyl ethyl ketone. Preferably the D90 is in the range of about 1500 μm to about 2000μm.
"Particle size distribution" means the cumulative volume size distribution of equivalent spherical diameters. The methodology and protocols for particle size distribution of R- rasagiline Mesylate by laser diffraction are described below: Instrument: Malvern Mastersizer 2000 Sample Handling Unit: Hydro2000S (A)
Range: 0.02μm to 2000μm; Pump/Stirrer Speed: 2800 RPM: Ultrasound: 10% Dispersant: Silicon oil Backgroud: With Dispersant
Sample Preparation: About 150mg of sample in beaker. Add 3-4 drops of silicon oil. Make a paste. Add 25ml of silicon oil and stir to mix well. Sonicate for 60 seconds. Obscuration: Between 10-20%
Optionally, the acid addition salt obtained can be purified further by recrystallization or slurrying in suitable solvents.
Suitable solvents in which the acid addition salt of R-rasagiline can be dissolved for purification include, but are not limited to C1-C5 ketones, such as acetone, ethyl methyl ketone, butanone and the like; alcohols, such as ethanol, methanol, and isopropanol: ethers, such as tetrahydrofuran, 1,4-dioxane. ethyl acetate and the like; water; and mixtures thereof. Preferably, acetone or water.

The product may optionally be further dried. Drying can be suitably 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 90°C. The drying can be carried out for any desired time until the required product purity is achieved.
In another aspect, the present invention provides propargylated aminoindans or a pharmaceutical])' acceptable salt thereof of formula I, having purity greater than about 98.5% as determined by chiral HPLC.
In a still further aspect, the present invention provides propargylated aminoindans or a pharmaceutically acceptable salt thereof of formula I, having purity greater than about 99% as determined by chiral HPLC.
In yet another aspect, the present invention provides propargylated aminoindans or a pharmaceutically acceptable salt thereof of formula I, having less than about 0.15 area % of (S)-isomer impurity as determined by chirai HPLC.
In yet another aspect, the present invention provides propargylated aminoindans or a pharmaceutically acceptable salt thereof of formula I. having less than about 0.1 area% of (S)-isomer impurity as determined by chiraf HPLC.
In another aspect, the present invention provides rasagiline or a pharmaceutically acceptable salt thereof having purity of about at least 98 area %, as determined by chirai HPLC.
In yet another aspect, the present invention provides rasagiline or a pharmaceutically acceptable salt thereof having purity of about at least 99 area %. as determined by chirai HPLC.
In another aspect the present invention provides rasagiline or a pharmaceutically acceptable salt thereof, having bisalkylated aminoindan or its enantiomer of structural


formula

and 1 -indanol of structural formula

each in an amount not more than about 0.15 area percent, as measured by HPLC.
In another aspect, the present invention provides rasagiline or a pharmaceutically acceptable salt thereof of, having bisalkylated aminoindan or its enantiomer of structural fonnula XII and 1-indanol of structural formula XIII, in an amount not more than about 0.1 area %, as measured by HPLC.
In a still another embodiment, the present invention provides rasagiline or a pharmaceutical J y acceptabJe salt thereof, obtained by the processes herein described, having less than about 0.15 area % of any individual impurity and 0.5 area % or less of total impurities as measured by chiral HPLC.
In yet another aspect, the present invention relates to pharmaceutical composition comprising propargylated aminoindans or their pharmaceutically acceptable salts thereof, obtained by the processes of the present invention, and at least one pharmaceutically acceptable carrier.
The present invention provides propargylated aminoindans or a pharmaceutically acceptable salt thereof of formula I, obtained by the processes described herein are substantially crystalline or amorphous or mixtures thereof.
The present invention provides rasagiline or any of the pharmaceutically acceptable salts prepared in accordance with the present invention, contains less than about 0.5%, of the corresponding impurities as characterized by chiral HPLC , where the chromatogram is obtained from a mixture comprising the desired compound and one or more of the said impurities, preferably less than about 0.1%. The percentage here refers to weight percent obtained from the area % of the peaks representing the impurities. R-rasagiline and salts thereof also are substantially free of other process-related impurities.

The process of the present invention advantageously provides R-rasagiline or its pharmaceutically acceptable salts in relatively high purity, of greater than about 98 % and preferably greater than about 99% as determined by chiral HPLC.
The R-rasagiline or its pharmaceutically acceptable salts obtained by the processes of the present invention has residual organic solvent less than the amount recommended for pharmaceutical products, as set forth for example in ICH guidelines and U.S. Pharmacopoeia; the recommended amount is less than 5000 ppm for ethanol, isopropanol methanol, ethyl acetate and acetone less than 800ppm for toluene, dichloromethane, dimethyl formamide and diisopropyl ether. Preferably, the amount is less than about 3000 ppm residual organic solvent, more preferably less than about 2000 ppm residual organic solvent, most preferably, less than about 1000 ppm.
In yet another aspect, the present invention relates to pharmaceutical composition comprising propargylated aminoindans or their pharmaceutically acceptable salts thereof obtained by the processes of present invention and at least one pharmaceutically acceptable carrier as an active ingredient, in association with a pharmaceutically acceptable carrier,
The pharmaceutical composition comprising R-rasagiline or its pharmaceutically acceptable salts prepared by the processes of present invention may be formulated for oral administration to treat depression, Attention Deficit Disorder (ADD), Attention Deficit and Hyperactivity Disorder (ADHD). Tourett's Syndrome, Alzheimer's Disease and other dementias. Accordingly, D90 particle size of the unformulated rasagiline or pharmaceutically acceptable salts thereof used as starting material in preparing a pharmaceutical composition generally is less than 300 microns, preferably less than about 200 microns, more preferably less than 100 microns, still more preferably less than about 50 microns.
Any milling, grinding micronizing or other particle size reduction method known in the art can be used to bring the solid state rasagiline or its pharmaceutically acceptable salt thereof into any desired particle size range as set forth above.
Another aspect of the present invention is directed to a pharmaceutical dosage form containing rasagiline or its pharmaceutically acceptable salts thereof. The pharmaceutical dosage may be in any form, for example, compacted tablets, powder suspensions, capsules, and the like. The compositions of the present invention can be administered to humans and animals in such dosage forms as oral, rectal, parenteral (intravenous, intramuscular, or

subcutaneous), intracisternal, intravaginal, intraperitoneal, local (powders, ointments or drops), ophthalmic, transdermal, or sublingual forms or as a buccal or nasal spray. Oral dosage forms include, but are not limited to, pills, capsules, troches, sachets, suspensions, powders, lozenges, elixirs, tablets, capsules (including soft gel capsules), ovules, solutions, and the like which may contain flavoring or coloring agents, for immediate-, delayed-, modified-, or controlled-release such as sustained-, dual-, or pulsatile delivery applications. R-rasagiline or its pharmaceutically acceptable salt thereof prepared by the process as described herein also may be administered as suppositories, ophthalmic ointments and suspensions, and parenteral suspensions, which are administered by other routes. The most preferred route of administration of the rasagiline or its pharmaceutically acceptable salts thereof of the present invention is oral.
The active ingredient of the invention may also be administered via fast dispersing or fast dissolving dosage forms or in the form of high energy dispersion or as coated particles. Suitable pharmaceutical composition of the invention may be in coated or uncoated form as desired.
Tableting compositions may have few or many components depending upon the tableting method used, the release rate desired and other factors. For example, the compositions of the present invention may contain diluents such as cellulose-derived materials like powdered cellulose, microcrystalline cellulose, microfine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other substituted and unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents such calcium carbonate and calcium diphosphate and other diluents known to one of ordinary skill in the art. Yet other suitable diluents include waxes, sugars (e.g. lactose) and sugar alcohols like mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin.
Other excipients contemplated by the present invention include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone. low-substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings:

sweeteners; preservatives; pharmaceutical!}' acceptable dyes and glidants such as silicon dioxide.
Capsule dosages will contain the solid composition within a capsule which may be
coated with gelatin. Tablets and powders may also be coated with an enteric coating. The
enteric-coated powder forms may have coatings comprising phthalic acid cellulose acetate,
hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate,
carboxymethylethylcellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, they may be employed with suitable plasticizers and/or extending agents. A coated tablet may have a coating on the surface of the tablet or may be a tablet comprising a powder or granules with an enteric coating.
The processes for the preparation of propargylated aminoindans or their pharmaceutically acceptable salts thereof of the present invention are simple, eco-friendly, robust, reproducible and easily scalable.
Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the preparation of the composition and methods of use of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
The examples which follow will further illustrate the preparation of the compound of the invention. These examples are not intended to limit the scope of the invention as defined hereinabove.
EXAMPLES
COMPARATIVE EXAMPLE: PREPARATION OF RACEMIC RASAGILINE prepared as in United States Patent 5,532,415
1-Aminoindane (100 g, 0.75mol), propargyl chloride (56 g, 0.75mol). potassium carbonate (104 g, 0.75 mol) and acetonitrile (800) were charged in a clean and dry 4 neck round bottom flask and the reaction mixture was stirred at about 55°C for about 24 hrs.

Thereafter, reaction mass was cooled to about 25°C, filtered, and the residue was washed with acetonitrile (200 ml). The resultant filtrate was concentrated under reduced pressure at about 40°C to obtain 130 grams of the racemic rasagiline base as an oily residue. Purity by HPLC: Rasagiline base: 72.33 %, Unreacted 1-aminoindane: 14.97%, Bisalkylated 1-aminoindane 8.66%.
EXAMPLE 1: PREPARATION OF RACEMIC RASAGILINE
1-Indanone (50g; 0.38 mol), titanium(IV) isopropoxide (128.9g. 0.45 mol) and) propargyl amine (20.8g, 0.38 mol) were taken in absolute ethanol (500 ml) and the reaction mixture was stirred at about 25-30°C for 8h to obtain the titanium complex. Thereafter, this titanium complex is reduced by adding sodium borohydride (2l.45g, 0.56 mol) at about 25-30°C. The reaction mixture was further stirred at about 25-30°C for about 8 h. The reaction mass was quenched by adding in a mixture of aqueous ammonia solution (100ml) and ethyl acetate. The precipitated inorganic solid was filtered. The organic layer was separated. The organic layer was extracted with 16% w/w aqueous hydrochloric acid. The aqueous extract was basified to pH 7.5-8.0 with aqueous ammonia solution and extracted with cyclohexane. . The cyclohexane extract was concentrated at about 40-45°C to obtain the rasagiline base as oily residue. Purity by HPLC: 98%.
EXAMPLE 2: PREPARATION OF R-(+)-RASAGILINE TARTRATE.
Rasagiline base (85 g. 0.49 mol) and L(+)-Tartaric acid (112 g, 0.77 mol) were taken in isopropanol (1020 ml) and the reaction mixture was stirred at reflux temperature for about 30 minutes, Thereafter, the reaction mass was gradually cooled to about 25-30°C and stirred for about 1.0 hr. The precipitated R-(+)-Rasagiline tartrate salts was filtered, washed with isopropanol (85ml) and dried at about 50-55°C to obtain 36 gm of crude R-(+)-Rasagiline tartrate.
Crude R-(+)-Rasagiline tartrate (10.0 g) is suspended in methanol (160 ml) and heated to reflux temperature at about 60-65°C. The content was stirred at about 60-65°C to obtain a clear solution. Thereafter, mixture was cooled to about 0-5°C and stirred for about 30 minutes. The crystalline R-(+)-Rasagiline Tartrate salt was filtered and washed with

methanol (10 ml) and dried at about 50-55°C to obtain 8 g of Rasagiline tartrate. Purity by HPLC: 99.89%.
EXAMPLE 3: PREPARATION OF R-(+)-RASAGILINE MESYLATE.
R-(+) Rasagiline tartrate (20.0g, 0.081 mol) was dissolved in DM water (200 ml) and the pH of the solution was adjusted to about 8.5-9 by adding aqueous ammonia solution. The solution was extracted with cyclohexane and the organic layer was concentrated at about 40-45°C to obtain a oily residue (9 gm)(assay by HPLC 97.35%).The residue was dissolved in acetone at about 25-30°C and stirred with methane sulfonic acid (6.06 g. 1.20 mol) at 25-30°C for 2h The precipitated Rasagiline mesylate was filtered and dried at about 50-55°C to obtain 12 gm of Rasagiline mesylate. Purity by HPLC: 99.97%.
Particle size distribution: D10 = 16.79μm; D5o = 39.18pm D90 = 74.327 μ m.
EXAMPLE 4: PREPARATION OF R-(+)-RASAGILINE MESYLATE
R-(+) Rasagiline tartrate (150 g . 0.3047 mole) was dissolved in DM water (1.5 Ltr) and the pH of the solution was adjusted to about 9-10 using 25% aqueous ammonia solution (96ml).Thereafter the reaction mass was stirred for 15min and aqueous layer extracted with cyclohexane. The organic layer was distilled under reduced pressure at about about 40-45 C to obtain R-Rasagiline base as oily product 100 g, R-rasagiline base oil (100 g) was dissolved in methylethylketone (3.0 Ltr) and thereafter reaction mass was stirred for about 15 minutes. Thereafter methane sulphonic acid (67.36 g,0.700 mole) was added to reaction mass at about 25-30 C in about 10 min and the reaction mass was stirred for about 10-15 min. The reaction mass was heated to about 70-75 C. Thereafter dimineralized water (74ml) was added to reaction mass at temperature of about 70-75 C. The reaction mass was heated at reflux temp for about 15 min. The heating and stirring were stopped and reaction mass was allowed to cool to about 20-25°C. The reaction mass was maintained at temperature of about 20-25°C for about 12-14 hours. The reaction mass was filtered to obtain wet rasagiline mesylate salt which was dried under vacuum tray dryer at about 55-60°C, to obtain R-rasagiline mesyalte (105 g, 0.70w/w).HPLC purity > 99.50 %, Chiral purity > 99.50 % Particle size distribution: D10 = 109.59 urn; D50= 1042.80 μ m D90 = 1624 μm.

X- ray powder diffraction (XRD) pattern with characteristic peaks at about

Pos. |°2Th.l d-spacing [A] Rel.Int. [%]
4.S4 19.46 2.85
9.08 9.74 100
13.63 6.49 52.81
18.20 4.87 42.68
22.81 3.90 17.42
27.45 3.25 8.71
36.89 2.43 4.45
EXAMPLE 5: PREPARATION OF R-(+)-RASAGlLINE MESYLATE
A solution of R-(+) Rasagiline tartrate (15.0g) and methanesulphonic acid (6.0 g) in isopopanol (150 ml) was heated to reflux for about 30 minutes. The reaction was allowed to cool to room temperature and resulting precipitate isolated by suction filtration to give the R-(+)-N-propargyI-l-aminoindane Mesylate. Yield = 31.0 g.HPLC purity > 99.5 %: Chiral purity > 99.9 %.Particle size distribution: D10 = 41.43 μm; D50= 150.06 μm D90 = 380.68 μm. X- ray powder diffraction (XRD) pattern with characteristic peaks at about

Pos. [°2Th.| d-spacing |Aj Rel.Int. [%]
4.54 19.46 3.28
9.08 9.74 100
13.64 6.49 41.04
18.21 4.87 26.45
22.82 3.90 8.37
27.47 3.24 3.22
36.91 2.43 1.31

CLAIMS:
1. A process for the preparation of a compound of formula I


wherein R1 — H or
comprising:
a) reacting an indanone derivative or a salt thereof of formula II with the
propargylamine or.a salt thereof of formula III in the presence of a Lewis acid; and


b) subjecting the resultant reaction mixture to reduction.
2. The process as claimed in claim 1, wherein the reduction is carried out in the presence of an optically inactive reducing agent to form a compound of formula V.


wherein R1 is as defined in claim 1, and resolving the compound of formula V with a chiral resolving agent to form the compound of formula I.
3. The process as claimed in claim 1 wherein the reduction is carried out in the presence of
optically active reducing agent to form the compound of formula I.
4. The processes as claimed in claims 1 to 3, wherein the preferred compounds obtained are
rasagiline and ladostigil or pharmaceutically acceptable salts thereof.
5. The processes as claimed in claims 1 to 3. wherein the compounds obtained are
converted into pharmaceutically acceptable salts.
6. The process as claimed in claims 5. wherein the pharmaceutically acceptable salt is the
mesylate or tartrate salt.
7. The processes as claimed in claims 1-4, wherein the propargylated aminoindans or a
pharmaceutically acceptable salt thereof obtained has purity greater than about 98.5% as determined by chiral high performance liquid chromatography.
8. Rasagiline or a pharmaceutically acceptable salt thereof obtained having less than about
0.15 area % of any individual impurity and not more than about 0.5 area % of
total impurities as measured by chiral high performance liquid chromatography .
9. Rasagiline or a pharmaceutically acceptable salt thereof, having bisalkylated
aminoindan or its enantiomer of structural formula


and 1-indanol of structural formula

each in an amount not more than about 0.15 area %, as measured by high performance liquid chromatography .
10. A pharmaceutical composition comprising rasagiline or a pharmaceutically acceptable salts thereof of formula 1 obtained by the processes described above and at least one pharmaceutically acceptable carrier.