FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"AN IMPROVED PROCESS FOR THE PREPARATION OF SAFINAMIDE MESYLATE"
Enaltec Labs Pvt Ltd. an Indian Company, having its Registered Office at l7th Floor, Kesar Solitaire, Plot No.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India. pin Code: 400705
1. The following specification particularly describes the invention and the manner in which it is to be performed.

AN IMPROVED PROCESS FOR THE PREPARATION OF SAFINAMIDE MESYLATE
FILED OF THE INVENTION:
The present invention relates to an improved process for the preparation of safinamide and its pharmaceutical acceptable salts thereof comprises reacting compound of structural formula II with lithium borohydride in an organic solvent to get safinamide compound of structural formula V.

BACKGROUND OF THE INVENTION:
Chemically safinamide mesylate is a methane sulfonic acid salt of (S)-2-[4-(3-Fluorobenzyloxy) benzyl amino] propanamide and it is known form U.S. patent no. 5,236,957 and is represented by compound of structural formula I.

Safinamide is useful in treatment of CNS disorders, in particular epilepsy, Parkinson's disorder, Alzheimer's disorder, depression, restless legs syndrome and migraine.

U.S. patent no. 5,236,957 does not exemplify the process of preparing safinamide mesylate compound of structural formula I. However the analogous compound of structural formula III is being prepared by reducing compound of formula IV by sodium cyanoborohydride in dry methanol solvent.

The reduction of compound of structural formula IV with employing sodium cyanoborohydride reducing agent results an impure compound of structural formula III, which is being purified by employing column chromatographic technique. U.S. patent no. 5,236,957 described that Safinamide can be formed analogously, starting from the corresponding aldehyde and the appropriate rx-aminoamide.
U.S. patent publication no. 2009/0156678 describes a process for preparing safinamide compound of structural formula V by catalytic hydrogenation of compound of structural formula II with hydrogen gas in the presence of a heterogeneous catalyst in a protic organic solvent.
P.C.T publication no. 2009/074478 describes a process for preparing safinamide compound of structural formula V by reducing of compound of structural formula II with sodium borohydride or potassium borohydride in methanol. The sodium borohydride or potassium borohydride is being used either in solid form or in the form of a methanolic solution stabilized by addition of sodium or potassium hydroxide.
It has now been discovered that the large scale production of safinamide and its pharmaceutical acceptable salts thereof according to the methods described in the prior-art, produces following by-product of reactions, which needs to be removed by purification through crystallization and employing column chromatography technique.


Accordingly there is a need in the art, to develop an improved process for the preparation of safinamide and its pharmaceutical acceptable salts thereof.
OBJECT OF THE INVENTION:
A first aspect of the present invention is to provide a process of preparing safinamide and its pharmaceutical acceptable salts thereof comprising the steps of:
a. reacting (S)-2-(4-(3-fluorobenzyloxy) benzylideneamino) propanamide compound of
structural formula II with lithium borohydride in an organic solvent to get safinamide
compound of structural formula V.

b. isolating safinamide compound of structural formula V and
c. converting safinamide compound of structural formula V into its pharmaceutically
acceptable salts.

A second aspect of the present invention is to provide substantially pure safinamide and its pharmaceutical acceptable salts thereof prepared by a process comprising the steps of:
a. reacting (S)-2-(4-(3-fluorobenzyloxy) benzylideneamino) propanamide compound of
structural formula II with lithium borohydride in an organic solvent to get safinamide
compound of structural formula V.

b. isolating safinamide compound of structural formula V and
c. converting safinamide compound of structural formula V into its pharmaceutical^
acceptable salts.
STATEMENT OF THE INVENTION:
The applicant of the patent has serendipitously observed that reduction of a compound of formula II with lithium borohydride results into a substantially pure safinamide compound of structural formula V.
The compound of structural formula II may be formed by methods known in the art such as those described in U.S. patent publication no. 2009/0156678 and P.C.T publication no. 2009/074478, which are incorporated herein by reference only.
The compound of structural formula II may also be prepared by reacting L-alaninamide and 4-(3-fluorobenzyloxy) benzaldehyde in a protic organic solvent in the presence of organic base.
The examples of protic organic solvent may include alcohols.

The examples of alcohols solvent may include but not limited to methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol or mixture(s) thereof.
The examples of organic base may include but not limited to triethyl amine, diisopropyl ethyl amine, dibutyl amine, diethyl amine, n-butyl amine, dicyclohexyl amine or mixture(s) thereof.
The reaction of L-alaninamide and 4-(3-fluorobenzyloxy) benzaldehyde may be carried out at a temperature in the range of 20°C to 30°C for a period of 10 minutes to 30 minutes to get (S)-2-(4-(3-fluorobenzyloxy) benzylideneamino) propanamide compound of structural formula II.
The (S)-2-(4-(3-fluorobenzyloxy) benzylideneamino) propanamide compound of structural formula II may be isolated or may be used as such in the next step of reaction.
The reaction of (S)-2-(4-(3-fluorobenzyloxy) benzylideneamino) propanamide compound of structural formula II with lithium borohydride may be carried out in an organic solvent
The examples of organic solvent may include alcohols.
The examples of alcohols solvent may include but not limited to methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol or mixture(s) thereof.
The reaction of (S)-2-(4-(3-fluorobenzyloxy) benzylideneamino) propanamide compound of
structural formula II with lithium borohydride may be carried out at a temperature in the range of
-5°C to 15°C for a period of 1 hours to 3 hours to get safinamide compound of structural formula
V.
The safinamide compound of structural formula V may be isolated by concentrating the reaction
mixture under reduced pressure to get a residue compound.
The residue compound may be dissolved in a halogenated hydrocarbons solvent and the resulting solution may be washed with water.

The examples of halogenated hydrocarbons solvent may include dichloromethane, dichloroethane, carbon tetrachloride, chloroform or mixture(s) thereof.
The solution of safinamide compound of structural formula V in halogenated hydrocarbons solvent may be concentrated under reduced pressure and the resulting residue compound may be dissolved in an alkyl acetate solvents.
The examples of an alkyl acetate solvent may include methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate or mixture(s) thereof.
The solution of safinamide compound of structural formula V in an alkyl acetate solvent may be treated with methane sulfonic acid at a temperature in the range of 20°C to 75°C for 2 hours to 8 hours to get safinamide mesylate compound of structural formula I.
The safinamide mesylate compound of structural formula I may be isolated by the steps of filtration, centrifugation, washing, drying and combinations thereof.
The safinamide mesylate compound of structural formula 1 may be dried at a temperature in the range of 45°C to 70°C under reduced pressure.
The safinamide mesylate compound of structural formula 1 obtained by following the present invention is substantially free from following impurities of structural formula VI to X.


The limit of detection of compounds of structural formula VI to X is as follows: Compound of structural formula VI: 0.001% weight/weight by HPLC (herein after w/w) Compound of structural formula VII: 0.005% weight/weight by HPLC Compound of structural formula VIII: 0.005% weight/weight by HPLC Compound of structural formula IX: 0.001% weight/weight by HPLC Compound of structural formula X: 0.005% weight/weight by HPLC
The term "substantially pure safinamide and its pharmaceutical acceptable salts" described herein refers to the safinamide and its pharmaceutical acceptable salts having compounds of structural formula VI to X less than their detection limit.


The example of pharmaceutical acceptable salts of safinamide may be safinamide mesylate.
The safinamide mesylate compound of structural formula I obtained by following the present invention may be crystalline or amorphous in nature.
The present invention of preparing safinamide mesylate compound of structural formula I having following merits:
1. Avoids chromatographic purifications of intermediates and safinamide mesylate compound of structural formula I.
2. Process is easy to scale-up on commercial scale.
3. Economical as the practical yield (95%) of preparing safinamide mesylate compound of
structural formula I from 4-(3-fluorobenzyloxy) benzaldehyde is very high compared to the
prior art processes (70-80%).
4. Quality (HPLC purity: 99.94%) of the product is very high,

EXAMPLE:
In the following example, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example 1: Preparation of substantially pure safinamide mesylate
A solution of L-alaninamide (40.58gm) in methanol (405ml) was added triethylamine (24.78gm) at 20-25°C in 30 minutes and then 4-(3-fluorobenzyloxy) benzaldehyde (50gm) was added dropwise in the reaction mixture at 25-30°C and then resulting reaction mixture was stirred for 3 hours at the same temperature. The resulting reaction mixture was cooled to 0-5°C and then lithium borohydride (4.78gm) was charged over a period of one hour and then resulting reaction mixture was stirred for 30 minutes at 0-5°C. The resulting reaction mass was concentrated under reduced pressure at 40°C to get a residue. The residue was dissolved in methylene dichloride (350ml) and washed with water (500ml). The organic layer was concentrated under reduced pressure to get a residue compound. The residue compound was dissolved in ethyl acetate (1250ml) at 72°C and methane sulfonic acid (17.5gm) was charged into the reaction mixture. The resulting reaction mixture was stirred for 4 hours at 20-25°C and then resulting solids were filtered, washed with ethyl acetate (50ml) and dried at 50°C under reduced pressure. Yield: 82gm; Purity: 99.94% (By HPLC)
Compound of structural formula VI: Not detectable [LOD = 0.001% weight/weight by HPLC] Compound of structural formula VII: 0.01% w/w [LOD - 0.005% weight/weight by HPLC] Compound of structural formula VIII: 0.02% w/w [LOD = 0.005% weight/weight by HPLC] Compound of structural formula IX: 0.01% w/w [LOD = 0.001% weight/weight by HPLC] Compound of structural formula X; Not detectable [LOD = 0.005% weight/weight by HPLC]

WE CLAIM:
1. A process of preparing safinamide and its pharmaceutical acceptable salts thereof comprising the steps of:
a. reacting (S)-2-(4-(3-fluorobenzyloxy) benzylideneamino) propanamide compound of structural formula II with lithium borohydride in an organic solvent to get safinamide compound of structural formula V.

b. isolating safinamide compound of structural formula V and
c. converting safinamide compound of structural formula V into its pharmaceutically
acceptable salts.
2. A substantially pure safinamide and its pharmaceutical acceptable salts thereof prepared by a process comprising the steps of:
a. reacting (S)-2-(4-(3-fluorobenzyloxy) benzylideneamino) propanamide compound of structural formula II with lithium borohydride in an organic solvent to get safinamide compound of structural formula V.

b. isolating safinamide compound of structural formula V and
c. converting safinamide compound of structural formula V into its pharmaceutically
acceptable salts.

3. The process according to claim no. I or 2 wherein the reaction of (S)-2-(4-(3-fluorobenzyloxy) benzylideneamino) propanamide compound of structural formula II with lithium borohydride is carried out in an organic solvent.
4. The process according to claim no. 3 wherein the organic solvent is selected from the group comprising of methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol or mixture(s) thereof.
5. The process according to claim no. 1 or 2 wherein the reaction of (S)-2-(4-(3-fluorobenzyloxy) benzylideneamino) propanamide compound of structural formula II with lithium borohydride is carried out at a temperature in the range of-5°C to 15°C for a period of 1 hours to 3 hours to get safinamide compound of structural formula V.
6. The process according to claim no. 1 or 2 wherein safinamide compound of structural formula V is isolated by concentrating the reaction mixture under reduced pressure to get a residue compound, which is dissolved in a halogenated hydrocarbons solvent and the resulting solution is washed with water.
7. The process according to claim no. 6, wherein halogenated hydrocarbons solvent is selected from the group comprising of dichloromethane, dichloroethane, carbon tetrachloride, chloroform or mixture(s) thereof.
8. The process according to claim no. 1 or 2 wherein isolated safinamide compound of structural formula V is reacted with organic acid in alkyl acetate solvents to get pharmaceutically acceptable salts of safinamide compound of structural formula V.
9. The process according to claim no. 8, wherein organic acid is methane sulfonic acid and alkyl acetate solvents is selected from the group comprising of methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate or mixture(s) thereof.
10. A process of preparing safinamide and its pharmaceutical acceptable salts thereof as
herein described in example and specification.