FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
Complete Specification [See Sections 10 and rule 13]
Title: A process for preparation of R-(+)-N-Propargyl-l-aminoindane and its pharmaceutical^ acceptable salt.
Applicant: (a) INTAS Pharmaceuticals Limited
(b) Nationality: Indian _
(c) 2nd Floor, Chinubhai Centre,
Ashram Road, Ahmedabad 380009.
Gujarat. India.
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 process for the preparation of R (+)-N-propargyl-l-aminoindane (VI) known as Rasagiline and its pharmaceutically acceptable salt.
BACKGROUND OF THE INVENTION
Rasagiline chemically known as R-(+)-N-propargyl-l-aminoindane is an irreversible inhibitor of monoamine oxidase and is used as a monotherapy in early Parkinson disease or as an adjunct therapy in more advanced cases. Rasagiline was disclosed in US 5,457,133. Market approved dosage forms contain mesylate salt of rasagiline which was disclosed in US 5,532,415.
Various synthetic routes are reported for the preparation of rasagiline, yet commonly used processes entail 1-aminoindane as starting material either racemic or as R-enantiomer.
US 5,457,133 disclose preparation of rasagiline by reacting racemic or (R)-l-aminoindane with propargyl halide optionally in presence of a suitable solvent. The reaction is completed in 16 hrs. and the product needs to be purified by chiral preparative HPLC which can not be considered feasible for commercial scale.
Other preparation processes of Rasagiline are reported in US 5,599,991, WO 2009/081148 and US 20060199974 wherein propargyl benzene sulfonate, tosylate or methane sulfonyl anhydride is used as an alkylating agent. All these processes involve reacting 1-aminoindane with propargyl alkylating agent in presence of solvent like aetonitrile or toluene.

WO 2009/14/454 discloses reacting (R)-1-aminoindane with propargyl tosylate in presence of organic bases. The product obtained has 64-33% HPLC purity.
Another process for preparation of rasagiline as disclosed in US 7,375,249 involves reacting (S)-l-indanol with methane sulfonyl anhydride in presence of triethylamine and dichloromethane at a low temperature i.e.-29 °C.
The process disclosed in WO 2009/141737 exemplifies use of biphasic system for preparation of rasagiline. The biphasic system consists of water and toluene.
in an alternative process disclosed in WO 2009/081148 racemic 1-aminoindane or
its R enantiomer is reacted with an allyl halide, the resulting N-allyl 1-aminoindane
is reacted with halogenating agent to get halo derivative and further reacted with a
base to obtain pure N-propargyl 1-aminoindane. The process involves multiple steps
of halogenation and dehalogeantion.
CN 101381314 reports preparation of rasagiline base by first protecting primary amine group of 1-aminoindane followed by reaction with propargyl chloride and deprotection, thus additional steps of protection / deprotection makes the overall process cumbersome.
CN 101260048 discloses a preparation of rasagiline via 1-indanone by using chiral auxilary agents.
Another approach as reported in WO 02/068376 can be preparation of (R)-enantiomerically enriched 1-indanamine by reacting racemic N-benzyl-1-indanamine with (R,R)-tartaric acid, followed by catalytic hydrogenation and

converting the (R)-enantiomerically enriched i-indanamine to rasagiline or its salts. Thus involves multiple steps of protection/deprotection.
WO 2009/147430 discloses 2,3,4,6-di-0-isopropyliene-2-keto-L-gluconic acid salt of racemic aminoindane, the distereomeric salt is recrystallised from methanol and water. The free (R)-l-aminoindane obtained by neutralization has optical purity of 96.5% and chemical purity 99.95%.
Prior art processes involving other than racemic or R-l-aminoindane starting material suffers form the multi step processes which includes protection deprotection at different steps or stereo specific synthesis of intermediates.
Rasagiline base can be directly used for further processes or can be purified. Purification of base is reported in US 2010/0010095 which involves sublimation of rasagiline base and then recrystalizing from sublimed form the purified and isolated liquid base has more than 98% R enantiomer.
In case of racemic starting material enantiomeric resolution is required which can be accomplished by any conventional method for resolution.
The resolution can be attained by using optically active acids or other methods known in the art. Generally tartaric acid is used for this purpose. The tartarate salt of rasagiline can be optionally purified or recrystallised from solvents such as methanol, isopropanol or mixture as disclosed in US 6,630,514, US 5,532,415 and US 5,599, 991, WO 2009/08118, US 2007/012217. US 7,491,847 discloses process for isolation of tartarate salt of rasagiline and also reports recrystallisation from water.

Rasagiline base can be converted into its methane sulfonic acid salt. Preparation of rasagiline mesylate is reported in many prior art patents such as US 5,532,415, US 2003/212145, US 2006/199974. Generally the salt is prepared using isopropanol as solvent, WO 2009/141737 uses non-hydroxylate solvents for salt preparation.
Although several different approaches for preparation of rasagiline are reported yet the process starting with racemic 1- aminoindane appears to be commercially most feasible.
All the reported methods used organic solvents in the condensation of 1-aminoindane with propargyl alkylating agent and need purification at different stages of process.
Needless to say it is advantageous to develop a simple and efficient process for preparation of rasagiline while using the inexpensive and readily available reagents without compromising the overall yield and purity of the compounds prepared.
Thus the present invention provides a process for preparation of rasagiline comprising reacting racemic 1-aminoindane with propargyl methane sulfonate in presence of the most inexpensive and readily available reaction medium i.e. water.
Use of water in place of organic solvent makes the process exceptionally simple, safe and environment friendly. This completely eliminates the need of solvent recovery and provides a non hazardous alternative for the synthesis of Rasagiline.

OBJECTS OF THE INVENTION
The main object of the present invention is to provide a process for preparation of Rasagiline, without using organic solvent in the condensation of 1-aminoindane with propargyl methane sulfonate.
Another object of the present invention is to provide cost effective, non hazardous and efficient process for preparing Rasagiline.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides a process for preparation of Rasagiline comprising reacting racemic 1-aminoindane with propargyl methane sulfonate in presence of water.
In another embodiment the process provides enantiomerically pure Rasagiline which comprises reacting racemic 1-aminoindane hydrochloride of formula (III) with propargyl methane sulfonate of formula (II) in presence of water and inorganic base, followed by resolution of propargyl aminoindane of formula (IV). The enantiomerically pure rasagiline of formula (VI) is then converted to its methanesulphonic acid salt.
DETAILED DESCRIPTION:
Accordingly, the present invention provides a process to prepare rasagiline as depicted by the following scheme:


The process involves reaction of racemic 1-aminoindane with propargyl methanesulfonate in water and in the presence of an inorganic base.
Propargyl methane sulfonate, can be prepared by generally known processes or the process provided by present invention.
The process of present application to prepare propargyl methane sulfonate includes reacting propargyl alcohol with methane sulfonyl chloride. The reaction is carried out in presence of a base wherein preferably triethyl amine is used. The solvent for the reaction can be selected from any suitable organic solvent like halogenated solvent; preferably dichloromethane. The isolation is effected by subjecting the reaction mixture to layer separation, and concentrating the organic layer.
The propargyl methane sulfonate as prepared above is then reacted with racemic 1-aminoindane or hydrochloride in water in the presence of an inorganic base.
The base used in the reaction is selected appropriately from inorganic class of compounds. The most preferred bases are metal carbonates, metal bicarbonates and metal hydroxides for example potassium carbonate, sodium carbonate, sodium

bicarbonate, sodium hydroxide or potassium hydroxide. The base is used in an amount although not limited to, equal or greater than molar equivalents relative to the starting intermediate of the formula (III), preferably in a range between 1 to 3 moles, more preferably 2 moles.
On completion of the reaction product is isolated by adjusting the pH of reaction mixture followed by extraction by an organic solvent. The solvent used for extraction can be selected from alkyl acetate such as ethyl acetate, dichloromethane, toluene, ketonic solvents such as methyl isobutyl ketone, ethers such as diisopropyl ether, tert. butyl methyl ether preferably toluene and/or dichloromethane; hydrocarbons hexane , heptanes more preferably cyclohexane . The racemic rasagiline base (IV) thus obtained is isolated as liquid and taken for further reactions preferably without drying or solidification and further purification as well.
The racemic Rasagiline base (IV) is further resolved to obtain R-(+)-Rasagiline, by treating the racemic mixture with an optically active acid, followed by diastereomeric crystallization.
Suitable optically active acids for resolution are selected from tartaric acid, camphor suphonic acid; mandelic acid wherein tartaric acid is especially preferred. The solvent for resolution is selected from protic solvents. The preferred solvent is isopropanol or aqueous isopropanol. The product obtained by using aqueous isopropanol for resolution is enantiomerically highly pure. The optically enriched diastereomeric salt is crystallized by cooling the reaction mixture. This is then isolated and from aqueous isopropanol, isopropanol and/or methanol to increase the optical / chiral purity, followed by treatment with an alkali to liberate free R (+)-N-propargyl-1-aminoindane. The alkali is selected from sodium hydroxide or

potassium hydroxide or any other metal hydroxides. The rasagiline base thus prepared is taken for further reaction without purification.
The pure Rasagiline base (VI) obtained by the process of present invention can be converted to its methane sulfonic acid salt. The process includes dissolving Rasagiline base (VI) in solvent selected from protic solvents, followed by addition of methane sulphonic acid preferably at a temperature in the range of 0-5°C, the reaction mixture is stirred at the same temperature, and the mesylate salt (VII) is isolated by filtration, the isolated product can be optionally washed with isopropanol and methyl tertiary butyl ether.
EXAMPLES
The above said invention can be illustrated by but not limited to following example(s).
Example 1: Preparation of Propargyl methane sulphonate
178 g of propargyl alcohol, 436 g of methane sulfonyl chloride 480 g of triethylamine and methylene dichloride 1246 ml were charged in a reaction flask at 20-25 °C. The temperature of reaction mixture was lowered to 0-5° C. Methane sulfonyl chloride was added drop wise at 0-5 °C while stirring and it was stirred at the same temperature for 5 hrs. After completion of the reaction, reaction mixture was filtered and the filtrate was cooled to 10-15°C. 356 ml of 10% hydrochloric acid was added to filtrate, layers separated and the organic layer was washed with demineralized water and concentrated under vacuum to get the title product in liquid form.

Yield = 295 g; HPLC purity: 98 %
Example 2: Preparation of racemic N-propagyl-1-aminoindan
6.34 g of 1-aminoindane hydrochloride, 30 ml demineralized water, 15.5 g potassium carbonates were charged in a reaction flask. The temperature of reaction mixture is increased to 70-75°C; propargyl mesylate was added drop wise at the same temperature while stirring. The reaction mixture was stirred at the same temperature for 7 hours. On completion of reaction, the temperature is lowered to 20-25 °C and 35 ml of water was added. The pH of the reaction mixture was adjusted to 1-1.5 by addition of concentrated hydrochloric acid. The reaction mixture was extracted with toluene and aqueous layer was collected. pH of aqueous layer was adjusted to 7.0-7.5 by using sodium hydroxide and reaction mixture was extracted with toluene. Layers were separated and organic layer was concentrated under vacuum to get the title compound as liquid.
Yield = 3.85 g, HPLC purity: 93%
Example 3: Preparation of racemic N-propargyl-1-aminoindan
50.0 g of 1-aminoindan hydrochloride, 250 ml demineralized water and 24.19 g sodium hydroxide were charged in a reaction flask. To this reaction mass, 43.51 g propargyl mesylate was added drop wise at 20-25°C. This reaction mixture was stirred at ambient temperature for 7.0 hours. After completion of reaction, pH was adjusted to 4.0 to 4.5 by using acetic acid. The reaction mixture was extracted with cyclohexane and aqueous layer was separated. pH of aqueous layer was adjusted to 7.0 to 7.5 by using aqueous ammonia. At this pH, reaction mixture was extracted

with cyclohexane. Layers were separated and organic layer was concentrated under vacuum to get the title compound as Jiquid.
Yield = 30.7 g, HPLC purity 97%
Example 4: Preparation of tartarate salt of racemic N-propargyl-1-aminoindan
4.0 g of racemic rasagiline base, 0.98 g of L-(+)-Tartaric acid, 40 ml. isopropanol (IPA) were charged in a reaction flask. Temperature of reaction mixture was increased to reflux and maintained at the same for 30 minutes. Once the reaction was completed the temperature was lowered to 20-25°C and stirred for 30 minutes at the same temperature. The reaction mixture was filtered and residue washed with 12 ml isopropanol.

Yield = 2.73g
Example 5: Purification of tartarate salt of racemic N-propagyl-1-aminoindan
2.73 g of tartarate salt, 40 ml isopropanol, 40 ml of methanol were charged in a reaction flask. Reaction mixture was heated to reflux and maintained at the same for 30-35 minutes, and then it is cooled to 25-30°C and stirred at the same temperature for 30 minutes. Reaction mixture was filtered and residue dried to get title compound.
Yield = 1.73 gm; Chiral purity: 99.5%
Example 6: Preparation of tartarate salt of racemic N-propargyl-1-aminoindan and its purification

28.0 g of racemic rasagiline base, 7.36 g of L-(+)-tartaric acid and 280 ml aqueous IPA (8 %) were charged in a reaction flask. Temperature of reaction mixture was increased to reflux temperature and maintained at the same for 30 minutes. After that, temperature was lowered to ambient temperature and stirred for 30 minutes at the same temperature. The reaction mixture was filtered and to this 224 ml aqueous IPA (10 %) was added. Temperature of reaction mixture was increased to reflux temperature and maintained at the same for 30 minutes. Then, temperature was lowered to ambient temperature and stirred for 30 minutes at the same temperature. The reaction mixture was filtered and residue was washed with 28 ml aqueous IPA (10 %).
Yield = 15.6 g, Chiral purity - 98.5 %
Example 7: Preparation of R (+)-N-propargyI-l-aminoindane
1.73 g of rasagiline tartarate, 8 ml of water were charged in a reaction flask. The temperature of reaction mixture was increased to 40-45°C. Sodium hydroxide was added at the same temperature till the pH of reaction mixture was 12.5 and stirred for 15 minutes. 16 ml of toluene was added to the reaction mixture. After separation of layers toluene layer was concentrated to yield title compound as liquid.
Yield 1.13 g
Example 8: Preparation of R (+)-N-propargyl-l-aminoindane Mesylate
Rasagiline base 1.13 g, isopropanol 5.65 ml were charged in a reaction flask. The reaction mixture was cooled to 0-5°C; methane sulfonic acid was added at the same

temperature. After completion of reaction, reaction mixture was filtered to get title compound.
Yield 1.7gm; Optical purity: 99.8%

We claim:
1. A process for preparing rasagiline or its pharmaceutical 1 y acceptable salts
comprising:
a. reacting racemic 1 -aminoindane or its salt with propargyl methane
sulfonate in water to get racemic rasagiline;
b. optionally resolving rasagiline obtained in step a);
c. optionally converting rasagiline to pharmaceutically acceptable salt.
2. A process as claimed in claim 1, wherein step a) is carried out in presence of inorganic base.
3. A process as claimed in claim 1 or 2 wherein the base is selected from sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.
4. A process as claimed in claim 1, wherein resolution in step b) is carried out in presence of optically active resolving agent.

5. A process as claimed in claim 1 or claim 4, wherein resolution is carried out in presence of aqueous isopropanol.