FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
PATENTS RULES, 2006
COMPLETE SPECIFICATION (SECTION 10; RULE 13)
"A PROCESS FOR THE PREPARATION OF N-PROPRAGYL 1-AMINO INDANE AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF."
ALKEM LABORATORIES LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, HAVING ITS CORPORATE. OFFICE AT ALKEM HOUSE, DEVASHISH, ADJACENT TO MATULYA CENTRE, S.B.MARG, LOWER PAREL, MUMBAI - 400013, MAHARASHTRA, INDIA
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

FIELD OF THE INVENTION
The present invention is directed to a process for the preparation of N-propargyl 1 -amino indane and pharmaceutically acceptable salts thereof.
BACKGROUND OF THE INVENTION
R (+)-N-propargyl-l-aminoindan (hereinafter referred to as R (+) PAI or rasagiline), having formula


has been reported to be a selective inhibitor of the B-form of the enzyme
monoamine oxidase ("MAO-B") and is useful in treating Parkinson's disease and various other conditions.
Rasagiline mesylate is approved for treating Parkinson's disease either as monotherapy or as an adjunct with other treatments. See, e.g. AGILECT®, Physician's Desk Reference (2007), 61st Edition, Thomson Healthcare.
U.S. Patent No. 5,532,415 ( hereinafter referred to as US'415 ) assigned to Teva Pharmaceutical Industries, discloses R (+)-N-propargyl-l-aminoindan, its preparation, and various pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions containing the same. Example 4 of US'415 teaches a process for the preparation of R-(+)-N-Propargyl-l-aminoindan by reacting R-(-)l-aminoindan with propargylchloride in the presence of potassium carbonate base in acetonitrile.However the '415 patent discloses isolation of the free R-(+)-N-propargyl-1-aminoindan base as an 'OIL'by chromatographic purification technique alone.
U.S. Patent No. 7,750,051 .{herein referred to as US'051} assigned to Teva Pharmaceutical Industries, Ltd. provides crystalline R(+)-N-propargyl-l-aminoindan [rasagiline], pharmaceutical compositions and methods of manufacture thereof.
According to the teachings of the '051 patent, the previously isolated rasagiline free base existed as an 'oil' due to presence of residual solvents and therefore the '051 patent attempted to provide a method to convert rasagiline free base as a 'Pure OIL' to a 'Pure SOLID Crystalline' form.

Examples 1 to 3 of US'051 teach a method to isolate rasagiline free base as a crystalline solid by basifying a cold aqueous solution of a salt of rasagiline by splitting and spontaneous crystallization from water while the other examples disclose a technique to isolate rasagiline free base as a crystalline solid by addition of water to an alcoholic solution of rasagiline free base. Although US'051 teaches a technique for the isolation of rasagiline free base in crystalline solid form, the free base of rasagiline employed by US'051 was prepared by a process as per US'415 and isolated as an 'OIL' by column chromatographic techniques alone. Thus US'051 essentially teaches a technique to convert rasagiline free base in an 'OIL' form to 'CRYSTALLINE' form-however it fails to provide a solution to isolate rasagiline free base of acceptable purity directly from the crude reaction mixture or without column chromatographic techniques and the like.
U.S. patent application publication No.US20090318564 assigned to Teva Pharmaceuticals Ltd discloses crystalline R (+) -N-propargyl-1-aminoindane containing water at an amount of less than 0.5% by weight. However this application too fails to solve the problem of arriving at rasagiline free base in pure form directly from the reaction mixture without column chromatographic purification or solvent re-crystallisation techniques. Instead, it attempts to convert an 'OIL' form of rasagiline free base to a 'SOLID Crystalline* form.
U.S. patent application publication No.US20100029987 assigned to Dipharma Francis relates to a novel process for the preparation of rasagiline or a salt thereof by reacting 1-indanone with propargyl amine, in the presence of a mixture of sodiumborohydride and acetic acid, to obtain N-propargyl 1-amino indane; and its conversion to a salt thereof. It also provides a process for the isolation of rasagiline free base in solid crystalline form with its characteristic XRPD values by cooling a solution of the crude free rasagiline base as an oil or by adding an anti solvent or also by basifying an acid addition salt of rasagiline free base in a mixture of water and organic solvent and crystallizing the residue of rasagiline free base from an aprotic apolar solvent. US20100029987 teaches various techniques and a variety of solvents to convert rasagiline free base as an 'OIL' to 'SOLID crystalline' form—however it fails to provide a solution to arrive at rasagiline free base of acceptable purity fit enough to be used for the next stage of conversion to its pharmaceutically acceptable salt directly from the reaction mixture without solvent re-crystallisation or complex column chromatographic purification techniques.
International patent application publication No.WO2010/013048 relates to novel crystalline form of rasagiline mesylate whiles another International patent application publication No.

WO2009/147432 provides a novel process for the preparation of rasagiline by reacting 1-amino
indane with a propargyl compound H-C = C -CH2X, or a protected form thereof, in the presence
of an organic base preferably Dabco, DBN, or most preferably DBU.
The process as devised by the present inventors does not necessitate the use of complex organic
bases, rather commercially available bases of the like of potassium carbonate could be used as
well.
It would be well appreciated by a person skilled in the art that the purity of the intermediate rasagiline free base and not its physical state of existence—'Solid' or 'Oil' is a critical parameter to the final purity and form of the subsequently formed salts of the like of rasagiline mesylate and that the physical state of the intermediate rasagiline free base is immaterial as long as this free base is obtained in a pure form in a simple and cost-effective manner to afford the final end product -ie; its pharmaceutically acceptable salt of desired form and purity. Thus there is an urgent need in the art for an industrially amenable process for rasagiline free base and its pharmaceutically acceptable salts in a cost effective manner devoid of the drawbacks of the prior art. The inventors of the present invention have succeeded in devising a novel eco-friendly process for preparing rasagiline free base and pharmaceutically acceptable salts thereof using reagents and solvents in a time and cost-effective manner at an industrially applicable scale. The present inventors have succeeded in isolating rasagiline free base of purity as high as 99 % by a selective solvent extraction technique directly from the crude reaction mixture unlike the prior art processes wherein tedious column chromatographic purification strategies or solvent re-crystallisation processes for the isolation of pure rasagiline free base were inevitable steps for purification of rasagiline free base.
The inventors of the present invention have developed a process of isolation of rasagiline free base with the primary goal of achieving rasagiline free base of high purity and yield by a workup based on selective solvent extraction directly from the crude reaction mixture devoid of complex column chromatography or re-crystallization methods.
SUMMARY OF THE INVENTION
A main aspect of the present invention is to provide a process for the preparation of N-propargyl 1- amino indane and its pharmaceutically acceptable salts, by a simple process of purification of N-propargyl amino indane free base, which is free of the above-mentioned disadvantages, starting

with commercially available materials and using simple reagents and low cost solvents, to afford high overall yield and purity of the product.
The reaction mixture comprising N-propargyl-1 -amino indane may be from a reaction obtained by any suitable prior-art process, for example by a process according to U.S.Pat.no.5,532,415.
The term "1-aminoindan" as used herein throughout the description and claims implies 1-aminoindan and/or any salt, solvate, stereoisomers or polymorphic form thereof, unless otherwise specified. The term "rasagiline" as used herein throughout the description and claims implies rasagiline and/or any salt, solvate, stereoisomers or polymorphic form thereof, unless otherwise specified. The current invention is particularly useful for the preparation of rasagiline free base.
The term 'exclusive' implies that the rasagiline free base was purified by selective solvent extraction technique alone and the conventional column chromatographic extraction or re-crystallisation methods were not used.
Thus according to an aspect of the present invention is provided rasagiline free base of purity as high as 99% directly from the crude reaction mixture by a workup by selective solvent extraction.
Thus according to an important aspect of the present invention is provided a process for the purification of N-propargyl-1-amino indane free base exclusively by selective pH adjustment and selective extraction.
Thus according to an aspect of the present invention is provided rasagiline free base of purity as high as 99% directly from the crude reaction mixture by a simple workup comprising selective solvent extraction.
The key aspects of the present invention can be summarized by the following steps:
A. A process for the preparation of N-propargyl-1-amino indane and its pharmaceutically
acceptable salts thereof comprising
a) providing a reaction mixture comprising N-propargyl-1-amino indane and/or a salt thereof,
b) purifying N-propargyl-1-amino indane free base exclusively by selective pH adjustment and selective extraction,
c) optionally isolating N-propargyl-1-amino indane free base or converting insitu to its pharmaceutically acceptable salt thereof.

B. A process according to A above, wherein the purification of N-propargyl-1 -amino indane
free base comprises the steps of
a) optionally removing the reaction solvent, adding water and extracting the reaction mixture with an organic solvent,
b) adjusting pH of the reaction mixture to about 1.0 to 5.0 , and optionally seperating the organic layer,
c) adjusting pH of the aqueous layer to about 3.0 to 14.0, and optionally seperating the aqueous layer,
d) optionally isolating N-propargyl aminoindane free base and/or converting N-propargyl aminoindane free base insitu to its pharmaceutically acceptable salt thereof.
C. A process according to B above, wherein the preferred pH in step b) is about 2.0 to 3.0 and
more preferably about 2.5 to 3.0.
D. A process according to B above, wherein the preferred pH in step c) is about 4.0 to 11.0 and
more preferably about 4.5 to 5.0.
E. A process for the purification of N-propargyl 1-amino indane free base comprising the steps
of
a) providing a reaction mixture comprising N-propargyl-1-amino indane and/or a salt thereof in
an organic solvent,
b) optionally removing the reaction solvent from the reaction mixture, adding water and
extracting the reaction mixture with an organic solvent,
c) adjusting pH of the reaction mixture to about 1.0 to 5.0, and optionally seperating the organic layer,
d) adjusting pH of the aqueous layer to about 3.0 to 14.0, and optionally seperating the aqueous layer,
e)optionally isolating N-propargyl aminoindane free base and/or converting N-propargyl
aminoindane free base insitu to its pharmaceutically acceptable salt thereof.
F.A process according to E above, wherein the preferred pH in step c) is about 2.0 to 3.0 and
more preferably about 2.5 to 3.0.
G. A process according to E above, wherein the preferred pH in step d) is about 4.0 to 11.0 and
more preferably about 4.5 to 5.0.
H. A process according to A and E above, wherein N-propargyl amino indane free base has a
purity of about 99%.

The following are the advantages in the process of the present invention:
• It provides a process which is eco-friendly, economical, and industrially applicable.
• It uses commercially available materials, reagents, low costs solvents and reduced number of steps.
• A reduced time-cycle and consequently a very fast and efficient synthetic process with a critical control of the impurity profile of the resultant products having a very high chemical and optical purity.
• It avoids tedious and time-consuming column chromatographic purification & solvent re-crystallisation techniques for the purification of rasagiline free base, instead uses simple workup techniques to arrive at rasagiline free base of high purity directly from the crude reaction mixture.
DETAILED DESCRIPTION OF THE INVENTION
Before the present process and methods are described, it is to be understood that this invention is not limited to particular compounds, formulas or s described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds and reference to "the " includes reference to one or more and equivalents thereof known to those skilled in the art, and so forth.
The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.
A main aspect of the present invention is to provide a process for the preparation of N-propargyl 1- amino indane and its pharmaceutically acceptable salts by purification of N-propargyl amino indane free base, which is free of the above-mentioned disadvantages, starting with commercially available materials and using simple reagents and low cost solvents, to afford high overall yield and purity of the product.
The reaction mixture comprising N-propargyl-1-amino indane may be from a reaction obtained by any suitable prior-art process and evident to a person skilled-in the-art, for example by a process according to U.S.Pat.no.5, 532,415.
Thus according to an important aspect of the present invention is provided a process for the purification of N-propargyl-1-amino indane free base exclusively by selective pH adjustment and selective extraction.
Thus according to an aspect of the present invention is provided rasagiline free base of purity as high as 99% directly from the crude reaction mixture by workup based on selective solvent extraction.
In accordance with the above objective, one aspect thereof, of the present invention provides a process for the preparation of N-propargyl-1-amino indane and pharmaceutically acceptable salts thereof by a process of purification of N-propargyl amino indane free base directly from its crude reaction mixture comprising the steps of a) providing a reaction mixture comprising N-propargyl-1-amino indane and/or a salt thereof,

b) purifying N-propargyl-1 -amino indane free base exclusively by selective pH adjustment and selective extraction,
c) optionally isolating N-propargyl-1-amino indane free base or converting insitu to its pharmaceutically acceptable salt thereof:
In accordance with the above objective, another aspect thereof, of the present invention provides a process for the purification of N-propargyl-1-amino indane directly from its crude reaction mixture comprising the steps of
a) providing a reaction mixture comprising N-propargyl-1-amino indane and/or a salt thereof,
b) purifying N-propargyl-1-amino indane free base exclusively by selective pH adjustment and selective extraction,
c) optionally isolating N-propargyl-1-amino indane free base or converting insitu to its pharmaceutically acceptable salt thereof:
In accordance with the above objective, another aspect thereof, of the present invention provides a process for preparing rasagiline and pharmaceutically acceptable salts thereof comprising
a) providing a reaction mixture comprising N-propargyl-1-amino indane and/or a salt thereof,
b) purifying N-propargyl-1-amino indane free base exclusively by selective pH adjustment and selective extraction,
c) optionally isolating the pure N-propargyl-1-amino indane free base or converting insitu to its pharmaceutically acceptable salt thereof:
In accordance with the above objective, still another aspect thereof, of the present invention provides a process for the purification of N-propargyll-amino indane directly from the crude reaction mixture comprising the steps of
a) providing a reaction mixture comprising N-propargyl-1-amino indane and/or a salt thereof in an organic solvent,
b) optionally removing the reaction solvent from the reaction mixture comprising N-propargyl 1-amino indane, adding water and extracting the reaction mixture with an organic solvent,
c) adjusting pH of the reaction mixture to about 1.0 to 5.0, and optionally seperating the organic layer,
d) adjusting pH of the aqueous layer to about 3.0 to 14.0, and optionally seperating the aqueous layer,

e)optionally isolating N-propargyl aminoindane free base and/or converting N-propargyl aminoindane free base insitu to its pharmaceutically acceptable salt thereof.
The reaction mixture comprising N-propargyl-1-amino indane may be from a reaction obtained by any suitable prior-art process and evident to a person skilled-in the-art, for example by a process according to U.S.Pat.no.5, 532,415.
The reaction solvent used may be any suitable solvent known in the prior art and evident to a person skilled in the art such as a nitrile, amide, hydrocarbon, ether, a ketone, an ester, alcohol and the like or mixtures thereof. In a preferred embodiment of the present invention, acetonitrile was used.
The reaction may be carried out at any temperature between ambient temperature and the boiling point of the solvent. The term ambient temperature in the present application is intended to indicate the temperature usually found in industrial laboratory and production facilities such as in the range of 15-40°C, preferably in the range of 20-30°C.
In a preferred embodiment of the present invention, R (+) N propargyl amino indane was prepared by heating a mixture of R (-) aminoindane HC1 with propargylchloride in the presence of potassium carbonate in acetonitrile at 60-62C.
In a preferred embodiment of the present invention, the crude reaction mixture containing the R (+) N propargyl amino indane was worked up by a process based on tactful pH adjustment of the aqueous and organic phases and selective extraction and wash techniques.
The extracting solvents used for the present invention may be selected from any conventional organic solvent used for extraction and apparent to a person skilled in the art such as halogenated solvents, esters, aliphatic or aromatic hydrocarbons, ethers and the like or mixtures thereof. Solvents of the like of Dichloromethane, Chloroform, Ethyl acetate, Toluene, Xylene, diethyl ether and the like or mixtures thereof apparent to a person skilled in art may be used.
In a preferred embodiment of the present invention, the reaction solvent-acetonitrile was distilled off under vacuum at 60-65deg C. The reaction mixture was cooled to room temperature, water was added and the residue stirred for about 20 mins.

An aspect of the present invention, provides a purification process of N-propargyl-1-amino indane having a purity as high as 99% directly from the crude reaction mixture by extraction of the crude reaction mixture with suitable conventional organic solvents and by tactful adjustment of the pH of the aqueous reaction mixtures with an acid to about 1.0 to 5.0, preferably 2.0 to 3.0 and more preferably about 2.5 -3.0.The acid used may be selected from any conventional inorganic or organic acids of the like of HC1 or methane sulfonic acids and the like and thus well known to a skilled person. The aqueous layer may be washed with the extraction solvent to facilitate extraction of organic impurities of the reaction mixture into the organic extraction solvent which may be discarded.
The pH of aqueous reaction mixture may be adjusted to about 3.0 to 14.0, preferably about 4.0 to 11.0 and more preferably about 4.5 to 5.0 by addition of an aqueous solution of a base and subjected to extraction with an organic solvent The base may be any conventional base such as an organic base or an inorganic base. In an embodiment of the present invention, a 50% aqueous solution of Potassium carbonate was used.
The combined organic extracts may be washed with an aqueous solution of a base to a pH of about 11.0 to 14.0, preferably 10.5-11.0, and the aqueous layer separated.The unreacted 1-amino indane present in the aqueous layer may be recovered back by extraction with an organic solvent.
In embodiments of the present invention, rasagiline free base of exceptional purity as high as 99% was isolated by distillation of the combined organic extracts.
Thus according to an aspect of the present invention is provided rasagiline free base of purity as high as 99% directly from the crude reaction mixture by a workup based on selective solvent extraction and tactful pH adjustment of the aqueous and organic phases.
The rasagiline free base may be converted to the desired pharmaceutically acceptable salts. Salts of 1-aminoindan and rasagiline include acid addition salts with suitable acids, including but not limited to inorganic acids such as hydrohalogenic acids (for example, hydrofluoric, hydrochloric, hydrobromic or hydroiodic acid) or other inorganic acids (for example, nitric, perchloric, sulfuric or phosphoric acid); or organic acids such as organic carboxylic acids (for example, propionic, butyric, glycolic, lactic, mandelic, citric, acetic, benzoic, salicylic, succinic, malic or hydroxysuccinic, tartaric, fumaric, maleic, hydroxymaleic, mucic or galactaric, gluconic, pantothenic or pamoic acid), organic sulfonic acids (for example, methanesulfonic,

trifluoromethanesulfonic, ethanesulfonic, 2- hydroxyethanesulfonic, benzenesulfonic, toluene-p-
sulfonic, naphthalene-2-sulfonic or camphorsulfonic acid) or amino acids (for example,
ornithinic, glutamic or aspartic acid).
A preferred salt of rasagiline is the methanesulfonic acid addition salt, also called rasagiline
mesylate.
In a preferred embodiment of the present invention, pure rasagiline free base was converted to technical rasagiline mesylate by adding a solution of methanesulfonic acid in isopropyl alcohol to a solution of the rasagiline free base in isopropyl alcohol.
In a preferred embodiment of the process of the present invention, a mixture of R(-)amino indane, propargylchloride and base potassium carbonate in acetonitrile were refluxed and the progress of the reaction monitored by TLC and HPLC.The reaction solvent acetonitrile was distilled off under vacuum, the reaction mixture cooled, water added and extracted with DCM twice. The aqueous layers were discarded, and to the combined DCM layers, water added, pH was adjusted to 2.0 to 2.5 by adding MSA.The organic DCM layer was discarded, and the aqueous layer was adjusted to a pH of about 4.0 to 4.5 with 50% aqueous potassium carbonate solution and extracted thrice with DCM. The combined DCM layers were distilled under vacuum to afford rasagiline free base as an 'OIL'.A solution of MSA in IPA was added to the reaction mass and heated for around 30 minutes. The reaction mass was cooled to RT and then to about 10°C and maintained for 1 hr.The mass filtered under suction, finally washed with IPA and dried under vacuum to afford technical rasagiline mesylate of 99.9% purity.
The process of the present invention can be performed on an industrial scale.
Examples:
Although the invention has been described in terms of particular embodiments and applications, one of ordinary skill in the art, in light of this teaching, can generate additional embodiments and modifications without departing from the spirit of or exceeding the scope of the claimed invention. It should be emphasized that the above-described embodiments of the present invention, particularly any "preferred" embodiments, are merely possible examples of the invention of implementations, merely set forth for a clear understanding of the principles of the

invention. Accordingly, it is to be understood that the drawings and descriptions herein are preferred by way of example to facilitate comprehension of the invention and should not be construed to limit the scope thereof.
Example-1-Preparation of R(+) N propargvl amino indane
Acetonitrile (700.00ml), R (-) Aminoindan HC1 (50.00g) and Potassium carbonate (80.lg) were charged to a reactor provided with the CaCl2 (fused) guard tube and the reaction mass was heated to 60-62 deg C under stirring for 1 hr.Propargyl chloride (17.0 g) was added to the mass dropwise and the reaction mass maintained for 28 hrs. A sample of the rcn mass was analysed after 28 hrs.Acetonitrile was distilled off at 60-65 deg C under 200 mbar vacuum.The RM was cooled to 25-30 deg C, Water (510ml) was added to the residue and stirred for 20 mins.
The aqueous reaction mass was then extracted with Dichloromethane (1x383ml; 1x125 ml) & the DCM. layer separated. 500 ml DM water was added to the combined Dichloromethane layer and the pH adjusted to 2.0-2.5 by adding 55ml (1:1 conc. HC1: DM water). The DCM layer was separated while the aq. Layer was extracted with DCM (3 X 500ml) and DCM layers discarded. The pH of aq. Layer was adjusted to 4.5-5.0 by addition of 40 ml of 50% aq. potassium carbonate solution. The aq. Layer was extracted with DCM (3x500ml).
500ml DM water was added to the combined DCM layers and a pH=10.5-l 1.0 was adjusted using 25ml of 50% aq. Potassium carbonate solution. DCM layer was separated and distilled out under vacuum to provide an Oily mass. Yield data: Rasagiline free base: 22.0 g Purity: 99.82%
Example-2-Preparation of R(+) N propargvl amino indane Mesylate
A solution of methanesulfonic acid (13.50g) in Isopropyl alcohol (100.00ml) was added drop wise to a solution of Pure Rasagiline free base (20.00g) in Isopropyl alcohol (100.00ml) at 25-27 deg C. The temperature was then raised to 35-38 deg C and the reaction mixture was heated to 60-65 deg C for 30 minutes to provide a clear solution. The hot bath was removed and the reaction mass was allowed to come to 28-30 deg C.The reaction mass was cooled tolO +1-2 deg C and the mass maintained for 1 hr.
The mass was filtered under suction, the bed washed with chilled (-2 to 0 deg C) Isopropyl alcohol and dried in oven at 85-90 deg C. Yield 17.8g Purity: 99.99 %.
Example-3-Preparation of rasagiline mesylate.

300ml DM water was added to the combined DCM layers and a pH=10.5-l 1.0 was adjusted using 25ml of 50% aq. Potassium carbonate solution. DCM layer was separated and distilled out under vacuum to provide an Oily mass. A solution of 5.0ml MSA in 50ml IPA was added to the reaction mass and heated to about 60-65C for around 30 minutes to get a clear solution. The reaction mass was cooled to RT, and further to about 10°C and maintained for 1 hour. The reaction mass filtered and dried to afford Rasagiline Mesylate of purity 99.88%.Yield-25.20gm.
Example-5 Process for the preparation of Rasagiline Mesylate.
Acetonitrile (50.7ml), R (-) Aminoindan HC1 (5.0g), Propargyl chloride (1.8g) and Potassium carbonate (8.9g) were charged and the reaction mass maintained to 60-62 deg C for 20 hrs. Acetonitrile was distilled off at 60-65 deg C. The RM was cooled to 25-30 deg C, Water (50ml) was added to the residue and stirred for 20 mins.
The aqueous reaction mass was then extracted with Dichloromethane (1x38ml; 1x8 ml) & the DCM layer separated. 25ml DM water was added to the combined Dichloromethane layer and the pH adjusted to 2.0-2.5 by adding 45ml Methanesulfonic acid. The DCM layer was separated while the aq. Layer was extracted with MDC (3 X 10ml) and DCM layers discarded. The pH of aq. Layer was adjusted to 4.5-5.0 by addition of 5 ml of 50% aq. potassium carbonate solution. The aq. Layer was extracted with DCM (2x 10ml). The combined DCM layer was distilled out and further stripped out by 5 ml isopropanol and 20 ml Isopropanol was added to dissolve the residue. The temperature was then raised to 35-38 deg for 30 minutes. The reaction mass was cooled to 10 +/-2 deg C and the mass maintained for 1 hr. filter the solid and wash the bed with chilled 25 ml isopropanol and dried to afford Rasagiline Mesylate of purity 99.95%.Yield-3.0gm

WE CLAIM:
l.A process for the preparation of N-propargyl-1-amino indane and its pharmaceutically acceptable salts thereof comprising
a) providing a reaction mixture comprising N-propargyl-1-amino indane and/or a salt thereof,
b) purifying N-propargyl-1-amino indane free base exclusively by selective pH adjustment and selective extraction,
c) optionally isolating N-propargyl-1-amino indane free base or converting insitu to its pharmaceutically acceptable salt thereof.
2. A process according to Claim 1 , wherein the purification of N-propargyl-1-amino indane free base comprises the steps of
a) optionally removing the reaction solvent, adding water and extracting the reaction mixture with an organic solvent,
b) adjusting pH of the reaction mixture to about 1.0 to 5.0 , and optionally seperating the organic layer,
c) adjusting pH of the aqueous layer to about 3.0 to 14.0, and optionally seperating the aqueous layer,
d) optionally isolating N-propargyl aminoindane free base and/or converting N-propargyl aminoindane free base insitu to its pharmaceutically acceptable salt thereof.
3.A process according to Claim 2 , wherein the preferred pH in step b) is about 2.0 to 3.0 and more preferably about 2.5 to 3.0.
4. A process according to Claim 2 above, wherein the preferred pH in step c) is about 4.0 to 11.0 and more preferably about 4.5 to 5.0
5. A process for the purification of N-propargyl 1-amino indane free base comprising the steps of
a) providing a reaction mixture comprising N-propargyl-1-amino indane and/or a salt thereof in
an organic solvent,
b) optionally removing the reaction solvent from the reaction mixture, adding water and
extracting the reaction mixture with an organic solvent,
c) adjusting pH of the reaction mixture to about 1.0 to 5.0, and optionally seperating the organic
layer,

d) adjusting pH of the aqueous layer to about 3.0 to 14.0, and optionally seperating the aqueous
layer,
e)optionally isolating N-propargyl aminoindane free base and/or converting N-propargyl
aminoindane free base insitu to its pharmaceutically acceptable salt thereof.
6.A process according to Claim 5, wherein the preferred pH in step c) is about 2.0 to 3.0 and more preferably about 2.5 to 3.0.
7. A process according to Claim 5 , wherein the preferred pH in step d) is about 4.0 to 11.0 and more preferably about 4.5 to 5.0.
8. A process according to Claims 1 and 5, wherein N-propargyl amino indane free base has a purity of about 99%.