Field of the Invention
The present invention relates to a novel process for the preparation of safinamide or acid addition salt thereof The present invention also relates to the process for the preparation of compound of Formula 17A, an intermediate of safinamide.
Background of the Invention
Safinamide is chemically known as (5)-2-[[4-[(3-fluorophenyl) methoxy]phenyl] methyl]aminopropanamide and has an empirical Formula of CnH]9FN202 and a molecular weight of 302.34 and shown in Formula 1:
Formula 1
The product is marketed in the form of mesylate salt. The pharmaceutical product containing this drug is sold in United States under the name Xadago, is a drug used as an add-on treatment for Parkinson's disease during "off episodes; it has multiple modes of action, including the inhibition of monoamine oxidase B.
Safinamide mesylate is used to treat idiopathic Parkinson's disease as add-on for people taking a stable dose of levodopa (L-dopa) alone or in combination with other Parkinson drugs, to help with "off episodes when levadopa stops working.
Safinamide and pharmaceutically acceptable salts thereof were first disclosed in US5236957. Example 1 of said patent described analogues process for preparing of safinamide by suspending glycinamide hydrochloride in dry methanol and sodium cyanoborohydride was added while stirring under nitrogen. After solubilization of the mixture 4-((3-fluorobenzyl)oxy)benzaldehyde was added in a single portion. The reaction mixture stirred and allowed to stand. The solution is filtered and evaporated, taken up with water and extracted three times with methylene chloride. After drying and evaporating, the crude residue is chromatographed on silica gel (eluant: chloroform/methanol/conc. NH4OH; 97/3/0.3) to give safinamide as shown in scheme 1:

Safinamide -
This process employed the use of sodium cyanoborohydride results an impure compound safinamide was obtained, which was purified by employing chromatographed on silica gel.
US8076515 disclosed a process for the preparation of high purity safinamide by first reacting 4-hydroxybenzaldehyde of Formula 5 with 3-fluorobenzyl chloride of Formula 4 to obtain 4-(3-fluorobenzyloxy) benzaldehyde of Formula 4, then treating with L-alaninamide hydrochloride of Formula 3 to obtain a schiff base (S)-2-[4-(3 fluorobenzyloxy) benzylideneamino] propanamide of Formula 6 followed by catalytic hydrogenation with hydrogen gas in the presence of a heterogeneous catalyst in a protic organic solvent to obtained safinamide in a free base form, optionally converting said free base form to a salt thereof with a pharmaceutically acceptable acid as-shown in scheme 2:
US_94_75757-disclosed a process for the preparation of safinamide involves iodating 3-fluorobenzyl alcohol of Formula 7 to obtain corresponding iodo intermediate of Formula 8, which was further coupled with 4-(hydroxymethyl)phenol under basic condition to obtain (4-((3-fluorobenzyl)oxy)phenyl)methanol compound of Formula

.10, then iodating to form corresponding alkyl iodo compound of Formula 11, which was further coupled with N-nosyl protected compound of Formula 12 to obtain N-nosyl protected amino alcohol compound of Formula 13, which on oxidizing to obtain N-nosyl protected amino acid compound of Formula 14 and then amination to form N-nosyl protected safinamide of Formula 15 and finally converted to safinamide as per below mentioned Scheme 3:
Scheme 3.
The processes for the preparation of Safinamide and its intermediates described in the aforementioned prior art suffer from disadvantages such as the use of expensive reagents/compounds such as - sodium cyanoborohydride, N-nosyl protected compounds, heterogenous catalyst and use of unstable aldehyde intermediate which is susceptible to oxidation to corresponding acid, use of tedious and cumbersome procedures like multiple process steps, prolonged reaction time periods, column.

chromatographic purifications, multiple isolations/ N re-crystallizations, and thus resulting in a poor product yield and quality. Methods involving column chromatographic purifications are generally undesirable for large-scale operations, thereby making the process commercially unfeasible.
Many other patent publications have also been disclosed so far, which describes the process for the preparation of safinamide mesylate. Still there is a need to develop a simple, cost effective, high yielding and easy to implement on industrial scale-process for the preparation of safinamide or acid addition salt. Object of the invention
The principal object of the present invention is to provide a process for the preparation of safinamide or acid addition salt thereof, which alleviates the drawbacks of prior art processes.
^ ■ ■
One. object of the present, invention is to provide an improved, efficient, safe and convenient process for the preparation of safinamide or acid addition salt thereof.
.Another object of the present invention is to provide a process for preparation of safinamide mesylate by using compound of Formula 10.
Further, another object of the present invention is to provide a process for preparation
of compound of Formula 17A. '
Yet another aspect of the present invention is that wherein compound of Formula 17 A is used an intermediate for the preparation of safinamide. Summary of the invention
In accordance with principal embodiment, the present invention provides a process for the preparation of safinamide or acid addition salt thereof, comprising the steps of: a) coupling of 3-fluorobenzyl halide of Formula 16
Formula 16
wherein X is halogen selected from CI, Br, I or any other good leaving group
with 4-hydroxybenzyl alcohol of Formula 9 or substituted 4-hydroxy benzyl alcohol of Formula 9A using suitable base in presence of a suitable solvent,

optionally in the presence of catalyst, to provide compound of Formula 10 or substituted compound of Formula 10 A;
Formula 10
b) substituting compound of Formula 10 or 10A using suitable substituting agent in the presence of the suitable solvent, optionally using catalyst, to provide compound of Formula 17;
Formula 17
wherein X is halogen selected from CI, Br, I or any other good leaving group c) coupling of compound of Formula 17 with L-alaninamide hydrochloride of Formula 3,
Formula 3
using suitable base, optionally using catalyst, in the presence of a suitable solvent, to provide safinamide; and
d) optionally, converting safinamide into acid addition salt thereof
In accordance with one embodiment, the present invention provides a process for the preparation of safinamide or acid addition salt thereof comprising the steps of: a) coupling of 3-fluorobenzyl chloride of Formula 4
Formula 4
with 4-hydroxybenzyl alcohol of Formula 9 using suitable base in presence of a suitable solvent, optionally in the presence of catalyst, to provide compound of Formula 10;

Formula 10 b) halogenating compound of Formula 10 using suitable halogenating agent in the presence of the suitable solvent, optionally using catalyst, to provide compound of Formula 17 A;
Formula 17A
c) coupling of compound of Formula 17A with L-alaninamide hydrochloride of Formula 3,
Formula 3
using suitable base, optionally, using catalyst, in the presence of a suitable solvent, to provide safinamide; and
d) optionally, converting safinamide into acid addition salt thereof.
In accordance with one embodiment, the present invention provides a process for the preparation of safinamide or acid addition salt thereof comprising the steps of:
a) coupling of 3-fluorobenzyl chloride of Formula 4
Formula 4 with 4-hydroxybenzyl alcohol of Formula 9 using suitable base in presence of a suitable solvent, optionally in the presence of catalyst, to provide compound of Formula 10;

b) halogenating compound of Formula 10 using suitable halogenating agent in the presence of the suitable solvent and catalyst to provide compound of Formula 17A;
Formula 17A
c) coupling of compound of Formula 17A with compound of Formula 3 A,
Formula 3A
■/ ■
wherein R is selected from the group comprising of substituted or unsubstituted alkyl
or aryl
using suitable base, optionally using catalyst, in the presence of a suitable
solvent, to provide compound of Formula 18:
Formula 18
d) aminating compound of Formula 18 using suitable aminating agent, optionally using catalyst, in the presence of suitable solvent to obtain safinamide; and
e) optionally, converting safinamide into acid addition salt thereof.
In accordance "with another embodiment, the. present invention provides a process for the preparation of safinamide mesylate, comprising the steps of: a) coupling of 3-fluorobenzyl chloride of Formula 4
Formula 4
with 4-hydroxybenzyl alcohol of Formula 9 using potassium carbonate and potassium iodide in the presence of ethanol as solvent to provide compound of Formula 10;

Formula 10 b) chlorinating compound of Formula 10 using thionyl chloride and catalytic amount of dimethylformamide in the presence of the'dichloromethane as solvent to provide compound of Formula 17A; ^
Formula 17A
c) coupling of compound of Formula 17A with L-alaninamide hydrochloride of
Formula 3, -
Formula 3
using calcium hydroxide, potassium iodide in the presence of dimethyl sulfoxide as solvent to provide safinamide; and d) finally, converting safinamide into its "mesylate salt using methane sulphonic acid.
In accordance with further another embodiment, the present invention provides a process for the preparation of compound of Formula 17A, comprising the steps of: a) coupling of 3-flu6robenzyl chloride of Formula 4
Formula 4 with 4-hydroxybenzyl alcohol of Formula 9 using potassium carbonate and potassium iodide in the presence of ethanol as solvent to provide compound of Formula 10;

Formula 10
b) chlorinating compound of Formula 10 using thionyl chloride amount of. dimethylformamide in the presence of the dichl solvent to provide compound of Formula 17A;
Formula 17A
In accordance with further yet another embodiment, .the present invention provides a process for the preparation of safinamide or acid addition salt thereof comprising the steps of:
a) chlorinating compound of Formula 10 using suitable chlorinating agent in the presence of the suitable solvent and optionally in presence of catalyst, to provide compound of Formula 17A;
b) coupling of compound of Formula 17A with L-alaninamide hydrochloride of Formula 3 using suitable base, optionally using, catalyst, in the presence of a suitable solvent, to provide safmamide; and
c) optionally, converting safinamide into acid addition salt thereof.
z' - . .
In accordance with further yet another embodiment, the present invention provides a process for the preparation safinamide mesylate comprising the steps of:
a) chlorinating compound of Formula 10 using thionyl chloride and catalytic
amount of dimethylformamide in the presence of the dichloromethane as
solvent to provide compound of Formula 17A;
Formula 17A

b) coupling of compound of Formula 17A with LTalaninamide. hydrochloride of Formula 3, using calcium hydroxide, potassium iodide in the presence of dimethyl sulfoxide as solvent to provide safinamide; and
c) finally, converting safinamide into its mesylate salt using methane sulphonic acid.
Yet another aspect of the present invention is that wherein compound of Formula 17
A is used an intermediate for the preparation of safinamide. Detail description of the drawings:
Fig.l is an illustration of an X-ray powder diffraction (XRPD) pattern of safinamide free base obtained according to example 3.
Fig.2. is an illustration of a Differential Scanning Calorimetry (DSC) of safinamide free base obtained according to example 3.
Fig.3. is an illustration of an X-ray powder diffraction (XRPD) pattern of safinamide mesylate obtained according to example 4.
Fig.4. is an illustration of a Differential Scanning Calorimetry (DSC) of safinamide mesylate obtained according to example 4. Detail description of the invention
The present invention provides an efficient and industrially advantageous process for the preparation of safinamide or acid addition salt thereof.
In accordance with principal embodiment, the present invention provides a process for the preparation of safinamide or acid addition salt thereof, comprising the steps of: a) coupling of 3-flubrobenzyl halide of Formula 16
Formula 16
wherein X is halogen selected from CI, Br, I or any other good leaving group with 4-hydroxybenzyl alcohol of Formula 9 or substituted 4-hydroxy benzyl . alcohol of Formula 9A using suitable base in presence of a suitable solvent, optionally in, the presence of catalyst, to provide compound of Formula 10 or substituted compound of Formula 10A;

Formula 10
b) substituting compound of Formula 10 or 10A using suitable substituting agent in the presence of the suitable solvent, optionally using catalyst, to provide compound of Formula 17;
Formula 17
wherein X is halogen selected from CI, Br, I or any other good leaving group
coupling of compound of Formula 17 with L-alaninamide hydrochloride of Formula 3,
Formula 3
using suitable base, optionally using catalyst, in the presence of a suitable solvent, to provide safinamide; c) optionally, converting safinamide into acid addition salt thereof.
In accordance with another embodiment, the present invention provides a process for the preparation of safinamide or acid addition salt thereof comprising the steps of: a) coupling of 3-fluorobenzyl chloride of Formula 4
Formula 4
with 4-hydroxybenzyl alcohol of Formula 9 using suitable base in presence of a suitable solvent, optionally in the presence of catalyst, to provide compound of Formula 10;

Formula 10
b) halogenating compound of Formula 10 using suitable halogenating agent in the presence of the suitable solvent, optionally using catalyst, to provide compound of Formula 17A;
Formula 17A
c) coupling of compound of Formula 17A with L-alaninamide hydrochloride of
Formula 3,
Formula 3
using suitable base, optionally using catalyst, in the presence of a suitable solvent, to provide safinamide;
d) optionally, converting safinamide into acid addition salt thereof.
^ First step involves coupling of 3-fluorobenzyl halide of Formula 16 or compound of Formula 4 with 4-hydroxybenzyl alcohol of Formula 9 or 9A using suitable base in presence of a suitable solvent, optionally in the presence of catalyst, to provide compound of Fohnula 10 or 10A. Generally reaction may be carried out at a temperature of 20 °C to reflux temperature for few minutes to few hours or till completion of the reaction. Preferably reaction is conducted at a temperature of 50 to 90°C, more preferably reaction is conducted at a temperature of 70 to 80°C and it takes 10 to 20 hours for completion^ the reaction,
wherein the substituted group of compound of Formula 9A can be selected from the group comprising of acyl and the like.
After completion of reaction, compound of Formula 10 or 10A is isolated or may be without isolation proceeds for the next step.

The suitable solvent used for coupling at step a) includes but not limited to organic solvents selected from the group comprising of alcohols, esters, ketone, nitrile, aliphatic or aromatic hydrocarbons* ethers, amides or mixture thereof. Preferably, selected from methanol, ethanol, isoproanol, n- propanol, ethyl acetate, propyl acetate, butyl acetate, acetone, propanone, butanone, methyl isobutyl ketone, acetonitrile (ACN), butyronitrile, acrylonitrile, toluene, xylenes, diethyl ether, methyl ter^-butyl ether (MTBE), diisopropyl ether, tetrahydrofuran (THF), dioxane, N;N-dimethylformamide (DMF), Af N-dimethylacetamide (DMAc), 7V-methylformamide and the like or mixture thereof, more preferably solvent used is ethanol or acetone.
The base used at step a) may be selected from organic or inorganic base, wherein inorganic base is selected from alkali or alkaline earth metal hydroxides, carbonates, bicarbonates selected from such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, calciumr carbonate, magnesium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, magnesium bicarbonate, cesium bicarbonate, sodium with liquid ammonia, sodamide, diisopropyl ethyl amine, triethyl amine, tributyl amine, TV-methyl morpholine, and pyridine and the like or mixture thereof; preferably base used is potassium carbonate.
The suitable catalyst used for coupling at step a) may be selected from the group comprising of sodium iodide, potassium iodide, cuprous iodide, sodium bromide, potassium bromide or phase transfer catalyst and the like; preferably eatalyst used is potassium iodide.
Next step involves substituting or halogenating compound of Formula 10 or 10A using suitable substituting or halogenating agent in the presence of the suitable solvent and catalyst to provide compound of Formula 17 or 17 A. Generally reaction may be carried out at a temperature of -10°C to reflux temperature for few minutes to few hours or till completion of reaction. Preferably reaction is conducted at a temperature, of 0 to 15°C, more preferably reaction is conducted at a temperature of 0 to 10°Cfor6to 10 hours.
The suitable substituting or halogenating agent at step b) may be selected from the group comprising of thionyl chloride, oxalyl chloride, PCb, PCI5, POCI3, TMSC1,

pivaloyl chloride, AICI3, SeGU, TiCU, CH3SO2CI and the like thereof, preferably halogenating agent used is thionyl chloride.
The suitable solvent for substitution or halogenation at step b) includes but not limited to alcohols, halogenated hydrocarbons, ethers, amides, hydrocarbons, ketone, esters and the like or mixture thereof Alcohols are selected from the group comprising of methanol, ethanol, w-propanol, isopropanol, w-butanol and the like. Halogenated hydrocarbons are - selected from the group comprising of dichloromethane (DCM), chloroform,
dichloroethahe, chlorobenzene and the like. Ethers are selected from the group comprising
1 of diethyl ether, methyl tert-buty\ ether (MTBE), diisopropyl ether, tetrahydrofuran
s (THF), dioxane and the like. Amides are selected from the group comprising of N,N-
dimethylformamide (DMF), A^TV-dimethylacetamide (DMAc), A^-methylformamide, N-
methylpyrrolidone and the like. Aliphatic hydrocarbons are selected from the group
comprising of alkanes or cycloalkanes such as pentane, hexane, heptane, octane,
cyclohexane, cyclopentane and the like. Aromatic hydrocarbons are selected from the
group comprising of toluene, xylene , acetone, propanone, butanone, methyl isobutyl
ketone, ethyl acetate, propyl acetate, butyl acetate and the like or mixture thereof.
Preferably, solvents used dichloromethane along with the catalytic amount of DMF.
f
After .completion of reaction, compound of Formula 17 or 17A is isolated or may be without isolation proceeds for the next step, which involves coupling of compound of , Formula 17 or 17 A with L-alaninamide Hydrochloride of Formula 3 or 3 A to provide safinamide or compound of Formula 18, is conducted using suitable base, optionally using catalyst in the presence of a suitable solvent. Generally this step may be carried out at a temperature of 20°C to reflux temperature for few minutes to few hours or till completion of reaction. Preferably this step is conducted at a temperature of 50 to 70°C, more preferably is conducted at a temperature of 40 to 50°C for 1 to 5 hours.
The compound of Formula 18 after isolation or without isolating is converted to safinamide using suitable animating agent, base, optionally using catalyst in the presence of suitable solvent to form safinamide.
The suitable solvent at step c & d) includes but not limited to water, alcohols, halogenated hydrocarbons, ethers, amides, sulfoxides, hydrocarbons, ketone, esters and the like or

mixture thereof? Alcohols are selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol and the like. Halpgenated hydrocarbons are selected from the group comprising of dichloromethane (DCM), chloroform, dichloroethane, chlorobenzene and the like. Ethers are selected from the group comprising of diethyl ether, methyl tert-bu\y\ ether (MTBE), diisopropyl ether, tetrahydrofuran (THF), dioxane and the like. Amides are selected from the group comprising of TV^A^-dimethylformamide (DMF), A/,7V-dimethylacetamide (DMAc), A^-methylformamide, dimethyl sulfoxide (DMSO), N-. methylpyrrolidone and the like. Aliphatic hydrocarbons are selected from the group comprising of alkanes or cycloalkanes such as pentane, hexane, heptane, octane, cyclohexane, cyclopentane and the like. Aromatic hydrocarbons are selected from the group comprising of toluene, xylene , acetone, propanone, butanone, methyl isobutyl ketone, ethyl acetate, propyl acetate, butyl acetate and the like or mixture thereof. Preferably, solvent used is dimethyl sulfoxide.
The base used at step c and d) may be selected from organic or inorganic base, wherein inorganic base is selected from alkali or alkaline earth metal hydroxides, carbonates, bicarbonates selected from- such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, cesium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, magnesium bicarbonate, cesium bicarbonate, sodium with liquid ammonia, sodamide, diisopropyl ethyl amine, triethyl amine, tributyl amine, iV-methyl morpholine- pyridine and the like or mixture thereof; preferably base used is calcium hydroxide.
The catalyst used at step c and d) may be selected from group comprising of sodium bromide, potassium bromide, potassium iodide, sodium iodide, cuprous iodide and the like thereof.
The suitable aminating agent used at step d) may be selected from group comprising of NH3 (gas), aq. ammonium hydroxides, NH3 solution in any solvent or agent that can deliver -NH2 group.
In accordance with further another embodiment, the present invention provides a process for the preparation of compound of Formula 17A, comprising the steps of:

a) coupling of 3-fluorobenzyl chloride of Formula 4
Formula 4
with 4-hydroxybenzyl alcohol of Formula 9 using potassium carbonate and potassium iodide in presence of ethanol as solvent to provide compound of Formula 10;

Formula 10
b) chlorinating compound of Formula 10 using thionyl chloride and catalytic amount of dimethylformamide in the presence of the dichloromethane as solvent to provide compound of Formula 17A;

Formula 17A
Yet another aspect of the present invention is that wherein compound of Formula 17 A is used an intermediate for the preparation of safinamide.
The solution of safinamide in any suitable solvent such as alkyl acetate may be treated
with methane sulfonic acid at a temperature in range of 50°C to reflux temperature for
few minutes to few hours or till completion of reaction. Preferably reaction is
conducted at a temperature of 60°C to reflux temperature, more preferably reaction is
conducted at a temperature of 60 to 70°C for 1 to 5 hours.
The alkyl acetate may be selected from but not limited to ethyl acetate, propyl acetate,
butyl acetate and the like or mixture thereof.
The safinamide mesylate obtained by the present invention is substantially free from
the impurities. Preferably, safinamide mesylate obtained by the present invention is
substantially free of the toxic impurity of Formula A:

Formula A
wherein said impurity is less than 0.05, preferably less than 0.03, more preferably less
than 0.01.
The present invention of preparing safinamide mesylate having following merits:
1. Avoids chromatographic purifications of intermediates and safinamide mesylate .
2. The process is conveniently scaled-up for industrial scale production of
safinamide or acid addition salt thereof. The process is simple economic with high
throughput, operationally efficient and environment friendly
3. Economical as the yield of safinamide mesylate is high compared to the prior art processes.
4. An intermediate l-((4-(chloromethyl)phenoxy)methyl)-3-fluorobenzene which is stable, stored and its quality can be improved by crystallization.
Although the following examples illustrate the present invention in more detail but the examples are not intended in any way to limit the scope of the present invention. It will thus be readily apparent to the one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modifications and variation of the concepts herein disclosed may be resorted to by those skilled in the art and that such modifications and variations are considered to be falling within the scope of the invention. Example 1
Preparation of (4-((3-fluorobenzyl)oxy)phenyl)methanol
The mixture of ethanol (500 ml), 4-hydroxybenzylalcohol (94 g) potassium carbonate (143 g) and potassium iodide (lg) was stirred for 1 hour at 25-30°C, then added 3-fluorobenzyl chloride (100 g) and heated the reaction mass to 75 to 80°C. The reaction mass was stirred at 75 to 80°C for 10 to 12 hours. After completion of the reaction, the reaction mass was cooled to 25 to 30°C and filtered. The filtrate was distilled off, to the residue dichloromethane (500 ml) was added and washed with DM water (250 ml x 2). Further, organic layer was concentrated, added MTBE (500 ml)

and stirred for 1 hour at 45 to 50°C. Slowly cooled reaction mixture to 25 to 30°C and stirred for 3 hours. Filtered, washed with MTBE (100 ml) and dried under vacuum to obtain the title compound. (Yield 145 g; HPLC purity > 98%) Example 2
Preparation of l-((4-(chloromethyl)phenoxy)methyl)-3-fluorobenzene The mixture of (4-((3-fluorobenzyl)oxy)phenyl)methanol (100 g), dichloromethane (500 ml), was cooled to 0-5°C and added DMF (0.5 ml). Then, added slowly thionyl chloride (61.5 g) while maintaining the temperature and stirred the reaction mass at 0 to 10°C for 6 to 8 hours. After completion of the reaction, concentrated the reaction mass and to the residue toluene (500 ml) and DM water (200 ml) was added. Further pH of the reaction mixture was adjusted 9 to 10 using 30% aq. potassium carbonate solution (100 ml). The layers were separated and washed the organic layer with DM water (250 ml x2). The organic layer was concentrated, MTBE (200 ml) was added and heated to 40 to 45°C and stirred. The reaction mass was cooled to 25 to 30°C, heptane (200 ml) was added and stirred for 30 minutes. Further cooled the reaction mass to 0 to 5°C and stirred for .6 hours. Filtered and dried under vacuum to obtain the title compound. (Yield 90 g, HPLC purity >98%) Example 3
Preparation for the preparation of safinamide
To the stirred mixture of L-alaninamide hydrochloride (44 g), calcium hydroxide (35.5 g) in DMSO (150 ml) was added KI (100 mg), temperature; of reaction mass * was raised to 45 to 50°C and stirred for 1 hour. A solution of l-((4-(chloromethyl)phenoxy)methyl)-3-fluorobenzene (30 g) in DMSO (60 ml) was added slowly while maintaining the temperature of the reaction and stirred the reaction mass at 45 to 50°C for 3 to 4 hours. The reaction mass was cooled to 10 to 15°C and DM water (840 ml) was added. Then, the reaction mass was stirred at 25 to 30°C for 2 to 3 hours, filtered, washed with DM water (60 ml x 2) and suck dried. To the wet cake DM water (150 ml) was added, stirred and adjusted the pH to 1-2 using 2N hydrochloric acid. The aqueous layer was washed with ethyl acetate (180 ml x 3). Further adjust the pH of aquebus layer to 9-10 using 30% aqueous-potassium carbonate solution and stirred for 3 hours at 25 to 30°C. Filtered, washed with water (60 ml x 2) and dried under vacuum to obtain the title compound. (Yield 27 g; HPLC. purity 99.5%)

Example 4
Preparation of Safinamide mesylate:
A mixture of safinamide free base (25g) in ethyl acetate (625 ml) was heated to 65 to 70 °C and stirred for 50 to 60 minutes at the same temperature to get a clear solution. To the reaction mass methanesulphonic acid (8.4 g) was added slowly and stirred for 1 to 2 hours. The reaction mass was slowly cooled to 25 to 30 °C and stirred for 4 to 5 hours. Filtered the product, washed with ethyl acetate and dried under vacuum to
obtain the title compound off white solid. (Yield 30 g; HPLC purity 99.5%)
i
Example 5
Preparation of (4-((3-fluorobenzyI)oxy)phenyl)methanoI:
To a mixture of 4-hydroxybenzyl alcohol (90 g) in acetone (600 ml) at 25 to 30°C was added potassium carbonate (124 g), potassium iodide (1 g) and 3-fluorobenzyl chloride (100 g). The temperature of reaction mixture was raised to 50 to 60 °C and stirred for 22 to 24 hour. After completion of the reaction, the reaction mixture was cooled to 40 to 45°C and acetone (300 to 350 ml) was distilled off under vacuum. Further, the. temperature of reaction mixture cooled to 25 to 30 °C, distilled water (1000 ml) was added and stirred for 2 to 3 hours. Filtered, wash with water DM water (100 ml X 2) and dried to obtain the crude product. To the crude product heptane (600 ml) was added and stirred at 25 to 30 °C for 2 to 3 hours. Filtered, washed with heptane.(100 ml X 2), and dried under vacuum to obtain the title compound. (Yield 145 g, HPLC purity > 98%). Example 6 Preparation of l-((4-(chloromethyl)phenoxy)methyI)-3-fluorobenzene:
A mixture of (4-((3-fluorobenzyl)oxy)phenyl)methanol (100 g) in dichloromethane (500 ml) was cooled to 0 to 5°C and added DMF (0.5 ml). To the reaction mixture thionyl chloride, (76 g) was added slowly. The reaction mass was stirred at 0 to 10°C for 6 to 8 hours and concentrated. To the residue dichloromethane (500 ml) and DM water (500 ml) was added, stirred, separate the layers. To the organic layer DM water (300 nil) was added, adjusted the pH of reaction mass to 8.5 to 9.0 using 30% aqueous potassium carbonate, stirred for 20 to 30 minutes and separate the layers . The organic layer so obtained was washed with water (250 ml) and distilled out the solvent to obtain the residue. To the residue heptane (400 ml) was added, heated to 45 to 50°C and stirred for 20 to 30 minutes. The reaction mass was cooled to 0 to 5°C and stirred

for 2 to 3 hours. Filtered, washed with chilled heptane (50 ml x 2) and dried under the vacuum to obtain the title compound. (Yield : 90 g; HPLC purity 99%) Example 7
Preparation of Safinamide free base:
To a mixture of L-Alaninamide hydrochloride (37 g) in N,N-Dimethyl acetamide (100 ml) was added lithium hydroxide monohydrate (37 g), sodium bromide (0.2 g) at 25 to 30 °C and stirred for 20 to 30 minutes. Further, the reaction mixture was heated at 60 to 70°C and a solution of l-((4-(chloromethyl)phenoxy)methyl)-3-fluorobenzene in N,N-Dimethyl acetamide (25 gm; 50 ml) was added slowly while maintaining the temperature of the reaction. After completion of the reaction, the reaction mass was cooled to 10 to 15 °C, DM water (600 ml) and stirred a room temperature. Filtered the product, washed with DM water and suck dried. To .the obtained wet cake DM water (125 ml) was added and pH of the reaction mass was adjusted to 2 to 2.5 using 3N hydrochloric acid (30 ml). Washed the aqueous reaction mixture with ethyl acetate (75 ml X 3). Further pH of the aqueous layer was adjusted to 9 to 9.5 with 30 % aqueous potassium carbonate solution (40 ml) and stirred for 2 to 3 hours. Filtered the product and washed with water and dried under vacuum to obtain the title compound as off white solid. (Yield 22g, HPLC purity 99.6%)

We claim:
1. A process for the preparation of safinamide or acid addition salt thereof, comprising
the steps of: a) substituting compound of Formula 10;
*
Formula 10
using suitable substituting agent in the presence of the suitable solvent, optionally using
catalyst, to provide compound of Formula 17; '
Formula 17
wherein X is halogen selected from CI, Br, I or any other good leaving group
b) coupling of compound of Formula 17 with L-alahinamide hydrochloride of Formula
3'
H2N>VH2 I HC1
Formula 3
. using suitable base, optionally using catalyst, in the presence of a suitable solvent, to provide safinamide;
c) optionally, coupling of compound of Formula 17 with compound of Formula 3 A,
Formula 3A
wherein R is selected from the group comprising of substituted or unsiibstituted alkyl or
aryl.
-using suitable base, optionally using catalyst, in the presence of a suitable solvent, to
provide compound of Formula 18:
Formula 18

aminating compound of Formula 18 using suitable aminating agent, optionally using catalyst, in the presence of suitable solvent to obtain safinamide; and d) optionally, converting safinamide into acid addition salt thereof.
2. The process as claimed in claim 1, wherein compound of Formula 10 is prepared
by coupling of 3-fluorobenzyl halide of Formula 16
Formula 16 wherein X is halogen selected from CI, Br, I or any other good leaving group with 4-hydroxybenzyl alcohol of Formula 9 or substituted 4-hydroxy benzyl alcohol 9A using suitable base in presence of a suitable solvent, optionally in the presence of catalyst, to provide compound of Formula 10;
wherein substituted 4-hydroxy benzyl alcohol compound of Formula 9A is selected from 4-(acyloxymethyl)phenol; optionally deprotecting when hydroxyl is protected,
3. The process as claimed in claim 1 and 2 for the preparation of safinamide or acid
addition salt thereof comprising the steps of:
a) coupling of 3-fluorobenzyl chloride of Formula 4
Formula 4
with 4-hydroxybenzyl. alcohol of Formula 9 using suitable base in presence of a suitable solvent, optionally in the presence of catalyst, to provide compound of Formula 10;
Formula 10
b) halogenating compound of Formula 10 using suitable halogenating agent in the presence of the suitable solvent, optionally using catalyst, to provide compound of Formula 17A;

Formula 17A
c) coupling of compound of Formula 17A with L-alahinamide hydrochloride of
Formula 3,
Formula 3
using suitable base, optionally using catalyst, in the presence of a suitable solvent, to provide safinamide; and
d) optionally, converting safinamide into acid addition salt thereof s
4. A process for the preparation of safinamide or acid addition salt thereof
comprising the steps of:
a) chlorinating compound of Formula 10 using suitable chlorinating agent in the presence of the suitable solvent and optionally in presence of catalyst, to provide compound of Formula 17A;
b) coupling of compound of Formula 17A with L-alaninamide hydrochloride of Formula 3 using suitable base, optionally using catalyst, in the presence of a suitable solvent, to provide safinamide; and
c) optionally, converting safinamide into acid addition salt thereof.

5. The process as claimed in claim 1 to. 4, wherein solvent is selected from group comprising of alcohols, esters, ketone, nitrile, aliphatic or aromatic hydrocarbons, ethers, amides, halogenated hydrocarbons, water, sulfoxides or mixture therefore and base is selected from inorganic or organic base.
6. The process as claimed in claim 1 to 4, wherein substituting agent or halogenating agent or chlorinating agent is selected from group comprising of thionyl chloride, oxalyl chloride, PC13, PCls, POCh, TMSC1, pivaloyl chloride, AICI3, SeCl4, T1CI4, CH3SO2CI; catalyst is selected from group comprising of sodium bromide, potassium bromide, potassium iodide, sodium iodide, cuprous iodide and aminating agent is selected from 'gr°uP comprising of NH3 (gas), aq. ammonium hydroxides, NH3 solution in any solvent or agent that can deliver -NH2 group.
7. A process for the preparation of safinamide mesylate, comprising the steps of:

a) coupling of 3-fluorobenzyl chloride _ of Formula 4 with 4-hydroxybenzyl alcohol of Formula.9 using potassium carbonate and potassium iodide in the presence of ethanol as solvent to provide compound of Formula 10;
b) chlorinating compound of Formula 10 using thionyl chloride and catalytic amount of dimethylformamide in the presence of the dichloromethane as solvent to provide compound of Formula 17A;
c) coupling of compound of Formula,. 1.7A with L-alaninamide hydrochloride of Formula 3 using calcium hydroxide, potassium iodide in the presence of dimethyl sulfoxide as solvent to provide safinamide; and
d). finally, converting safinamide into its mesylate salt using methane sulphonic acid.
8. The process for the preparation of safinamide, wherein the compound of Formula
17A is prepared by the process comprising the steps of:
a) coupling of 3-fluorobenzyl chloride of * Formula 4 with 4-hydroxybenzyl alcohol of Formula 9 using potassium carbonate and potassium iodide in the presence of ethanol as solvent to provide compound of Formula 10;
b) chlorinating compound of Formula 10 using thionyl chloride and catalytic amount of dimethylformamide in the presence of the dichloromethane as solvent to provide compound of Formula 17A.
9. A process for the preparation safinamide mesylate comprising the steps of:
a) chlorinating compound of Formula 10 using thionyl chloride and catalytic amount
of dimethylformamide in the presence of the dichloromethane as solvent to provide
compound of Formula 17A;
b) coupling of compound of Formula 17A with L-alaninamide hydrochloride of Formula 3, using calcium hydroxide, potassium iodide in the presence of dimethyl sulfoxide as solvent to provide safinamide; and
c) finally, converting safinamide into its mesylate salt using methane sulphonic acid.
10. The use of compound of Formula 17A as an intermediate for the preparation of
safinamide.