FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"PROCESS FOR THE PREPARATION OF AMINOINDANE COMPOUND"
2. APPLICANT:
(a) NAME: INDOCO REMEDIES LIMITED
(b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956
(c) ADDRESS: Indoco House, 166 C. S. T. Road, Santacruz (East), Mumbai - 400 098, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention and the manner in which it is to be performed.

Field of Invention:
The present invention relates to the process for the preparation of (R) - N- propargyl - 1 -aminoindane of Formula -1 and its pharmaceutically acceptable salts.
Background and Prior Art:
The compound (R) - N- propargyl - 1 - aminoindane of Formula -1, is commonly known as Rasagiline. The compound belongs to a class of drugs called monoamine oxidase inhibitors of type - B (MAO - B) useful for the treatment of dementia, Alzheimer's disease, depression in addition to treating Parkinson's disease.

Formula -1
Rasagiline was first described in patent US 5457133, wherein the compound (R) - N-
propargyl - 1 - aminoindane was prepared by reacting (R) - 1 - aminoindane with propargyl
chloride in presence of potassium carbonate and solvent acetonitrile for 16 hours to get (R) -
N- Propargyl - 1 - aminoindan free base. The free base is purified by flash chromatography
before converting to its pharmaceutically acceptable hydrochloride salt. Another method
disclosed to prepare the compound (R) - N- propargyl - 1 - aminoindane is by reacting
racemic 1- aminoindane with propargyl chloride in presence of potassium carbonate and
solvent acetonitrile for 16 hours to get N- Propargyl - 1 - aminoindan free base. The free
base is subjected to chromatographic resolution to separate (R) - N- Propargyl - 1 -
aminoindan before converting to its pharmaceutically acceptable hydrochloride salt.
The drawback of the process is that, .
• it takes longer time to complete the reaction; and
• it requires chromatographic resolution / purification to isolate the pure isomer;
Another process for the preparation of Rasagiline methane sulfonate is disclosed in patent US5532415, wherein the compound racemic 1 - aminoindane is reacted with

propargylbenzensulfonate in aqueous sodium hydroxide and toluene to get racemic N-Propargyl - 1 - aminoindan free base. The free base is resolved with L - tartaric acid to isolate distereomeric salt (R-(+)-N-propargyl-l-aminoindan)-L-tartrate which on reaction with methanesulphonic acid in isopropanol at reflux yields R-(+)-N-propargyl-l-aminoindan methanesulfonate. It is observed that during the reaction, impurities of dipropargyl indanamine are formed.
The drawbacks of the above process are poor yield of the product and the use of biphasic solvent system for the reaction.
Patent application WO2009081148 describes preparation of Rasagiline by reacting racemic 1 - aminoindane with allylbromide for 12-13 hours and isolating oxalic acid salt of N-allyl-2, 3-dihydro-1 H-inden-1 -amine oxalate. The compound N-allyl-2, 3-dihydro-1 H-inden-1 -amine oxalate on treatment with aqueous sodium hydroxide followed by bromination using liquid bromine yielded N-(2,3-dibromopropyl)-2,3-dihydro-1-H-inden-1-amine. The dibromo compound on treatment with base results in racemic rasagiline which is further, resolved with Tartaric acid to isolate (R)-(-)-N-propargyl-l-aminoindan)-L-tartrate. The tartrate salt is treated with base and reacted further with methane sulphonic acid to yield (R)-N-propargyl-1 -aminoindan methanesulfonate.
The drawbacks of the above process are;
• necessity of preparing salt and then free base increases the number of steps;
• longer duration of the reaction time and
• resolution of the final compound to isolate the required enantiomer.
Another method for the preparation of rasagiline is described in patent application WO02068376 wherein, 1 - indanone is reacted with benzylamine in presence of acetic acid followed by reduction with sodium borohydride in ethanol results in N - benzyl - 1 -indanamine. The compound N - benzyl - 1 - indanamine on resolution using tartaric acid yields (R)- N-benzyl-1-indanamine (R,R)-tartrate which on catalytic hydrogenation using 5%

Pd / C followed by treatment with base yields (R)-l-Ihdanamine. The enantiomeric rich (R)-I-Indanamine is reacted with propargyl sat to get (R)-N-propargyl-l -aminoindane. The draw back of the process is;
• the number of steps involved are more as it requires protection and deprotection of the intermediate;
Therefore, there remains a need for an improved process for preparing (R)-N-propargyl-l-aminoindane and its salt of Formula -1 that eliminates or substantially reduces the number of steps, longer reaction times and avoids chromatographic separation of required enatiomer of the product.
Thus, the present inventors have come out with an improved one pot process which ameliorates the problems in the prior art by using a catalyst to reduce the time of reaction and carrying out chemical purification thus avoiding the chromatographic separation of the required enantiomer.
Objective of the Invention:
The main objective of the present invention is to prepare (R)-N-propargyl-l-aminoindane and its pharmaceutically acceptable salt by robust, rigid and industrial friendly process.
Another objective of the present invention is to prepare (R)-N-propargyl-l-aminoindane in one pot process.
Another objective of the present invention is to prepare methanesulfonate salt of (R)-N-propar gy 1-1 -aminoindane,
Yet another objective of the present invention is to prepare pure (R)-N-propargyl-l-aminoindane with an improved purification process.

Summary of the Invention:

Comprising a step of;
reacting (R) -1 - aminoindane of Formula - II

Accordingly, the present invention provides a process for the preparation of (R)-N-propargyl-1-aminoindane of Formula -I and its pharmaceutically acceptable salt;
with propargyl derivative of Formula - III
Formula-III Wherein X = CI, Br and - ORr, Where R1 = mesyl, tosyl, p - methoxybenzensulfonyl, benzenesulfonyl,
o-or p-nitrobenzenesulfonyl;. in the presence of catalyst and non - polar solvent to give base (R)-N-propargyl-l-aminoindane.
Accordingly the present invention provides a process wherein the base (R)-N-propargyl-l-aminoindane is reacted with methanesulphonic acid in presence of solvent to isolate mesylate salt of (R)-N-propargy 1-1 -aminoindane of Formula -1.
Further the isolated salt is purified from suitable solvent to get pure (R)-N-propargyl-l-aminoindane methane sulphonate.

Detail Description of the Invention:
The present invention provides a one pot process for the preparation of (R) - N- propargyl -
1 - aminoindane of Formula -1 and its pharmaceutically acceptable salts:
In one embodiment of the present invention (R) -1 - aminoindane of Formula - II is reacted

with propargyl derivative of Formula - III

formula-ill Wherein X = CI, Br and - OR1; where R1 = rhesyl, tosyl, p - methoxybenzensulfonyl, benzenesulfonyl, o- or p - nitrobenzene sulfonyl, in non - polar solvent in presence of catalyst and base to give the compound (R)-N-:propargyl-l-aminoindarie of Formula -1. The compound thus obtained is reacted with methane suphonic acid in presence of solvent to isolate methane sulphonate salt of (R)-N-propargyl-l-aminoindane of Formula - I. The reaction sequence of the present invention is shown below as in scheme -1;

Accordingly in one of; the embodiment of the present invention, (R) -1 - aminoindane is reacted with propargyl derivative in non polar solvent in presence of a catalyst and a base, potassium carbonate, at temperature in the range of 20 - 60°C. The propargyl derivative used for the reaction is selected from chloro, bromo, mesylate, tosylate, benzenesulfonate, p -methoxybenzensulfonate and o- or p - nitrobeftzenesulfonate, wherein the preferred derivative used for the reaction is tosylate. The non polar solvent used for the reaction is selected from toluene, xylene, chlorobenzene, cyclohexane and heptane; wherein the preferred solvent used for the reaction is toluene. The catalyst used for the reaction is polar aprotic solvents selected from N,N-dimethylformamide, N - methylpyrollidine and N,N -dimethylacetamide, wherein the most preferred catalyst used for the reaction is N,N -dimethylformamide. The preferred ratio of the solvent to the catalyst used is 8:2, The temperature of the reaction is maintained in the range of 20 - 60°C, wherein the preferred temperature range for the reaction is 35 - 50°C; and the most preferred temperature range for the reaction is 40 - 45 °C. The time required for the completion of the reaction is 6 - 8 hours. Accordingly as per the present invention, (R) -1 - aminoindane and the base potassium carbonate is charged to the non polar solvent containing a catalyst, at temperature 20 - 30°C. The temperature of the reaction is raised to attain 45°C, and then started adding first lot of propargyl tosylate solution during 1.5 hours to 2.0 hours by maintaining temperature at 40 -45°C. The reaction is maintained at 40 - 45°C and monitored the reaction for unreacted propargyl tosylate limit to below 1.0%. Charged second lot of propargyl solution in 1.5 hours to 2.0 hours by maintaining temperature at 40 - 45°C. The reaction is maintained further for three hours by monitoring the unreacted propargyl tosylate limit to below 1.0%. It is observed by the inventors, when propargyl tosylate is charged in two lots, the consistency in the reaction result is very good, otherwise the addition of propargyl tosylate can be done in one lot and is not limited to lot: wise addition. When the lot wise addition of propargyl tosylate is carried out, the first lot contains.80% of propargyl tosylate quantity and the remaining 20% is added in second lot. After completion of the reaction the reaction mass is cooled to 25 - 30°C and quenched with water. The organic layer is separated and taken for work up. The organic layer is washed with water and taken for pH adjustment. Fresh water is charged to the organic layer and under stirring the pH of the solution is adjusted to acidic

using dilute solution of sulfuric acid. Aqueous layer is separated from the organic layer. The pH adjustment and extraction sequence is repeated to maximize the yield.
In another embodiment of the present invention, the pH of the aqueous layer is adjusted in the range of 3 - 3.5 using dilute solution of sodium hydroxide. The aqueous layer is extracted with solvent selected from toluene, methyl tertiary butyl ether, di isopropyl ether, and dichioromethane; wherein the preferred solvent used is methyl tertiary butyl ether. This step is necessary to make the aqueous solution free from dipropargyl impurity.
The pH of the aqueous layer is further adjusted to 7 - 7.5 using dilute sodium hydroxide solution at 25 - 30°C. After adjusting the pH, the aqueous solution is further extracted with solvent dichioromethane. The pH adjustment and the extraction process is repeated to maximize the yield of the product (R)-N-propargyl-l-aminoindane of Formula - I. To make the process economical and recycle, the solvent the extraction of aqueous layer is carried out in toluene instead of dichioromethane. The solvent is dried using anhydrous sodium sulphate and concentrated under reduced pressure to isolate the compound (R)-N-propargyl-l-aminoindane of Formula -1.
Yet another embodiment of the present invention, the compound (R)-N-propargyI-l-aminoindane Formula - I is reacted with methane sulphonic acid in mixture of non polar and polar solvent to isolate pharmaceutically acceptable methane sulphonate salt of the compound of Formula - I. The non polar solvent for the reaction is selected from toluene, xylene, chlorobenzene, cyclohexane and heptane, wherein the preferred non polar solvent used is toluene, xylene and chlorobenzene; and the most preferred non polar solvent used is toluene. The polar solvent used for the reaction is selected from C1 - C4 linear or branched chain alcohol. The preferred polar solvent used is selected from methanol, ethanol, propanol, isopropanol, butanol, sec. butanol and tert. Butanol; wherein the most preferred solvent used for the reaction is isopropanol. The ratio of polar to non polar solvent used is from 1: 10 to 4: 7,the preferred ratio of polar to non polar solvent used is 1: 10. The reaction is carried out at temperature in the range of 10 - 90°C.

Accordingly, the compound (R)-N-propargyl-l-aminoindane is charged in mixed solvent toluene and isopropanol and cooled to 10°C and started adding methane sulphonic acid solution prepared in mixed solvent by maintaining the temperature at 10°C - 15°C in 30 minutes to 1.0 hour. Gradually the temperature of the reaction mass is raised to 80 - 85°C and maintained at this temperature for 30 minutes to 1.0 hour. Stopped heating and cooled the reaction mass to 10°C and maintained under stirring for 2hrs, filtered the compound to isolate methane sulphonate salt of (R)-N-propargyl-l-aminoindane of Formula - I [Rasagiline mesylate],
In yet another embodiment of the present invention, the compound rasagiline mesylate is taken for purification in solvent at temperature range of 60 - 90°C. The solvent used for purification is selected from C1 - C4 alcohols, lower esters and hydrocarbons or mixture thereof. The preferred C1 - C4 alcohols used for purification are methanol, ethanol, propanol, isopropanol and butanol. The preferred esters used for the purification are ethyl acetate, propyl acetate, isopropyl acetate and methyl isopropyl acetate. The preferred hydrocarbons used for the purification are toluene, chlorobenzene, cyclohexane and tetrahydrofuran. The preferred solvents used for purification are methanol, isopropanol, ethyl acetate, methyl isopropyl acetate, toluene, and tetrahydrofuran or mixture thereof. The most preferred solvents used for purification are selected from isopropanol, ethyl acetate, and toluene or mixture thereof. The preferred temperature to carry out purification is in the range of 80 -85°G
According to the invention, the compound rasagiline mesylate is charged in solvent selected from toluene and ethyl acetate and heated to 80°C. Maintaining the temperature at 80 - 85°C; isopropanol is charged till clear solution is obtained. Maintained the temperature for 1- 2 hour at 80 - 85°C. After maintaining, the reaction is cooled to 25 - 30°C and further to 5°C. Maintained the reaction at 8 - 12°C for one hour and filtered the solid mass. Washed the product with mixed solvent used for purification and dried the compound at 60 - 65°C to get pure rasagiline mesylate.

The present invention is further illustrated in detail with reference to the following examples. . It is desired that the examples be considered in all respects as illustrative only and non restrictive to the invention.
EXAMPLES:
Example -1: Preparation of (R)-N-propargyl-l-aminoindane:
Charged (R)-l-aminoindane (25gm) in mixture of Toluene: DMF (125ml), stirred and charged anhydrous K2CO3 (31.12g). Raised the temperature of the reaction mixture to 40 -45°C. Prepared first lot propargyl tosylate solution in toluene: DMF (33.15gm in 50ml) mixture and added slowly within 1 to 2hrs at 40 - 45°C. Maintained the reaction mass under stirring for additional 2hrs at 40 - 45°C. Prepared second lot propargyl tosylate solution in toluene: DMF (8.3gm in 25ml) mixture and added slowly within 1 to 2hrs at 40 - 45°C. Maintained under stirring for additional 4hrs at 40 - 45°C. Cooled the reaction mixture to 25 - 30°C, charged water (250ml) and stirred for 15min. Separated organic layer, and the aqueous layer re-extracted with toluene (75ml x 2). Combined all toluene layers with organic layer and charged water (250ml). Adjusted the pH of the organic layer to 2 using dilute sulfuric acid solution, stirred, settled and separated the aqueous layer. Repeated the same process with another 120ml of water. Combined all aqueous layers and adjusted pH of the aqueous layer to 3 - 3.5 using dilute sodium hydroxide solution. Extracted the aqueous layer with methyl tertiary butyl ether (75ml). Further adjusted the pH of the aqueous layer with dilute sodium hydroxide solution till pH is 7 - 7.5. Extracted the aqueous layer with dichloromethane (125ml). Repeated the same process twice. Combined all dichloromethane layers, dried over anhydrous sodium sulphate and concentrated to get oily residue of (R)-N-propargyl-1-aminoindane. Yield = 20.9gm, % Yield = 65% HPLC purity = > 98.0%.

Example - 2: Preparation of Crude methane sulfonate salt of (R)-N-propargyl-l-aminoindane [Rasagiline Mesylate]:
Charged (R)-N-propargyI-l-aminoindane (5.38gm) and methaesulfonic acid (3.33gm) to mixture of solvent toluene: IPA (59.18ml) at 10°C and stirred for 15minutes. Raised the temperature of the reaction to 25 - 30°C and heated to attain 75 - 80°C. Maintained for 30 minutes and applied cooling to bring the temperature to 20 - 30°C and further to 10°C, stirred 2.0 hours at 10°C. Filtered and washed with cooled toluene: IPA mixture. Dried the solid product under reduced pressure at 60-65°C till constant weight. Yield = 7.98gm, % Yield = 95% HPLC purity = 99.5 - 99.8%.
Example - 3: Purification of Rasagiline mesylate:
Charged crude rasagiline mesylate (7.98gm) in ethyl acetate (79.8ml) and raised the temperature under stirring to 80-85°C. Slowly added isopropanol to the slurry maintaining temperature at 80-85°C till clear solution obtained. Stirred at 80 - 85°C for another 1.0 hour. Stopped heating and cooled the reaction mixture to 25 - 30°C, further to 10°C, and maintained for 2.0 hours. Filtered the solid and washed with cooled mixture of ethyl acetate and isopropanol (1:1). Dried pure rasagiline mesylate under reduced pressure at 60-65°C till constant weight. Yield = 6.783gm; % Yield = 85%; HPLC purity = 99.9-100%.
Example - 4: Preparation of Crude methane sulfonate salt of (R)-N-propargyl-l-aminoindane [Rasagiline Mesylate]:
Charged (R)-l-aminoindane (25gm) in mixture of Toluene: DMF (125ml), stirred and charged anhydrous K2CO3 (31.12g). Raised the temperature of the reaction mixture to 40 -45°C. Prepared first lot propargyl tosylate solution in toluene: DMF (33.15gm in 50ml) mixture and added slowly within 1 to 2hrs at 40 - 45°C. Maintained under stirring for additional 2hrs at 40 - 45°C. Prepared second lot propargyl tosylate solution in toluene:

DMF (8.3gm in 25ml) mixture and added slowly within 1 to 2hrs at 40 - 45°C. Maintained under stirring for additional 4hrs at 40 - 45°C. Cooled the reaction mixture to 25 - 30°C, charged water (250ml) and stirred for 15min. Separated organic layer, and the aqueous layer re-extracted with toluene (75ml x 2). Combined all toluene layers with organic layer and charged water (250ml). Adjusted the pH of the organic layer to 2 using dilute sulfuric acid solution. Stirred, settled and separated the aqueous layer. Repeated the same process with another 120ml of water. Combined all aqueous layers and adjusted pH of the aqueous layer to 3 - 3.5 using dilute sodium hydroxide solution. Extracted the aqueous layer with methyl tertiary butyl ether (75ml). Further adjusted the pH of the aqueous layer with dilute sodium hydroxide solution till pH is 7 - 7.5 and extracted with Toluene (125ml). Repeated the same process twice. Combined all toluene layers, dried over anhydrous sodium sulphate and filtered. Charged IPA (21ml) to the dried toluene layer and cooled to 10°C. Charged methaesulfonic acid (11.77gm) at 10°C and stirred for 15 minutes. Removed cooling and allowed the temperature of the reaction mixture to attain 25 - 30°C. Applied heating to raise the temperature to 75 - 80°C, maintained for 30 minutes and gradually cooled to 25 - 30°C and further to 10°C, stirred and maintained at 10°C for 2.0 hours. Filtered the product and washed with cooled toluene: IPA mixture. Dried the solid product under reduced pressure at 60-65°C till constant weight. Yield -31gm; %Yield-61.75%; HPLC purity = 99.5 - 99.8%.
Example -5: Purification of Rasagiline mesylate:
Charged crude rasagiline mesylate (2.1.0 gm) in toluene (210 ml) and raised the temperature under stirring to 80-85°C. To this slurry IPA was added slowly at 80-85°C to get clear solution and stirred for another l hour. Reaction mixture was allowed to cool to 25 - 30°C, further to 10°C and maintained for 2.0 hours. Filtered the solid and washed with cooled mixture of toluene and isopropanol (16.0 ml). Dried pure rasagiline mesylate under reduced pressure at 60-65°C till constant weight. Yield =18gm; % Yield = 85.71%; HPLC purity = 99.9 -100%.

We claim,
1. A process for the preparation of (R)-N-propargyl-1 -aminoindane of Formula - I and its pharmaceutical acceptable salt;

comprising a step of;
reacting (R) -1 - aminoindane of Formula - II

with propargyl derivative of Formula - III

Formula-III Wherein x = CI, Br and-OR,; Where R1 = mesyl, tosyl, p - methoxyberizensulfonyl, benzenesulfonyl,
o- or p - nitrobenzenesulfonyl; in presence of catalyst and non - polar solvent to yield (R)-N-propargyl-l-aminoindane of Formula-I. 2. The process as claimed in claim 1; wherein preparation of (R)-N-propargyl-l-aminoindane of Formula -1 comprises the following steps;
a. reacting (R) -1 - aminoindane of Formula - II with propargyl derivative in presence of catalyst and nonpolar solvent to yield (R)-N-propargyl-l-aminoindane of Formula -1;

b. reacting the compound (R)-N-propargy 1-1-amino indane with methane sulphonic
acid in presence of solvent to get methane sulphonate salt of (R)-N-propargyl-l-
aminoindane of Formula -1; and
c. purifying the salt obtained in solvent ethyl acetate, toluene and isopropanol or
mixture thereof, to isolate pure methane sulfonate salt of (R)-N-propargyl-l-
aminoindane.
3. The process as claimed in claims 1 and 2, wherein the catalyst used is polar aprotic solvent selected from N, N - dimethylformamide, N, N - dimethylacetamide. and N -methylpyrol lidine
4. The process as claimed in claim 3; wherein the preferred catalyst used for the reaction is N, N - dimethylformamide.
5. The process as claimed in claims 1 and 2, wherein the non polar solvents used for the reaction are selected from toluene, xylene, chlprobenzene, cyclohexane and heptane.
6. The process as claimed in claim 5, wherein the preferred solvent used for the reaction is toluene.
7. The process as claimed in claim 2, wherein the solvent used in step b for the salt formation is selected from non polar, and polar protic solvents.
8. The process as claimed in claim 7, the solvents used for the salt formation are selected from toluene, xylene, chlorobenzene, cyclohexane, heptane and C1 - C4 linear or branched chain alcohol or mixture thereof.
9. The process as claimed in claim 7, wherein the preferred solvent used for the salt formation are selected from toluene, xylene, chlorobenzene, cyclohexane, heptane, methanol, ethanol, propanol, isopropanol, butanol, sec. butanol and tert. Butanol or mixture thereof.
10. The process as claimed in claims 1 and 2, wherein the preparation of (R)-N-propargyl-l-aminoindane of Formula -1 comprising the steps of;
a. reacting (R) -1 - aminoindane of Formula - II with propargyl derivative at
temperature in the range of 20 - 60°C;
b. decomposing the cooled reaction mixture with water and separating the organic
layer;

c. adjusting the pH of the organic layer with dilute sulphuric acid upto 2.0 and
separating the aqueous layer;
d. adjusting the pH of the aqueous layer to 3 - 3.5 with dilute sodium hydroxide
solution and extracting with ethyl acetate or methyl tert. butyl ether;
e. further adjusting the pH of the aqueous layer with dilute sodium hydroxide
solution to 7-7.5;
f. extracting the aqueous layer with toluene or dichloromethane and separating the
organic layer;
g. concentrating the organic layer at 45 - 50°C under reduced pressure to isolate
(R)-N-propargyl-l-aminoindane of Formula -1.
h. reacting the compound (R)-N-propargyl-l-aminoindane with methane sulphonic
acid in presence of solvent to isolate methane sulphonate salt of (R)-N-propargyl-
1-aminoindane of Formula -1; and i. purifying the salt obtained in a solvent selected from ethyl acetate, toluene and
isopropanol either alone or a mixture thereof, to isolate pure methanesulfonate salt
of (R)-N-propargyl-l-aminoindane.
11. The process as claimed in claim 10; wherein the preferred temperature of the reaction in ste a is 35-50°C.
12. The process as claimed in claim 11; wherein the most preferred temperature of the reaction is 40 - 45°C.
13. The process as claimed in any one of the preceding claims, wherein the preferred propargyl derivative used for the reaction is propargyl tosylate.
14. The process as claimed in any one of the preceding claims, wherein the compound is methane sulfonate salt of (R)-N-propargyl-l-aminoindane.