FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE: IMPROVED PROCESS FOR PREPARING SAFINAMIDE
Solara Active Pharma Sciences Limited
An Indian company having its registered office at
201, Devavrata, Sector 17, Vashi, Navi Mumbai- 400 703,
Maharashtra, India
The following specification particularly describes the invention and the manner in
which it is to be performed:

FIELD OF THE INVENTION
The present application relates to an improved process for the preparation of Safinamide or a pharmaceutically acceptable salt thereof.
BACKGROUND OF THE INVENTION
Safinamide mesylate (XADAGO®) is a monoamine oxidase type B (MAO-B)
inhibitor indicated as adjunctive treatment to Jevodopa/carbidopa in patients with
Parkinson's disease (PD) experiencing "off" episodes. Safinamide mesylate is
chemically known as (S)-2-[[4-[(3-fluorophenyl)
methoxy]phenyl]methyl]aminopropanamide methanesulfonate (1:1). The chemical structure of Safinamide mesylate is represented as formula I

Safinamide, its R-enantiomer, their racemic mixture and pharmaceutically acceptable salts thereof and the use thereof for the preparation of pharmaceutical compositions active as anti-epileptic, anti-Parkinson, neuroprotective, antidepressant, antispastic and/or hypnotic agents is specifically described in WO 90/14334.
Synthesis of Safinamide, have also been described in various patent publications including WO 2007/147491, WO 2009/074478 and WO 2014/178083. However, there remains a need for an improved and efficient process for preparing Safinamide or a pharmaceutically acceptable salt thereof, in high yield and purity.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an illustration of a powder X-ray diffractogram (PXRD) Safinamide mesylate prepared according to Example 6.

SUMMARY OF THE INVENTION
The present invention aims to provide an improved process and efficient process for preparing Safinamide or a pharmaceutically acceptable salt thereof, in high yield and purity.
In an aspect, the present invention provides a process for preparing Safinamide or a pharmaceutically acceptable salt thereof of formula I,

the process comprising:
a) contacting a reaction mixture comprising a compound of formula II and a
suitable solvent,

with a bisulfite salt to form a compound of formula lla,

wherein, M is selected from the group consisting of hydrogen, lithium, sodium, potassium, ammonium and combination thereof;
b) reacting the compound of formula lla with L-Alaninamide or a salt thereof in
presence of a base to obtain a compound of formula III; and


c) reducing the compound of formula III, with a reducing agent or by catalytic reduction, to provide Safinamide or a pharmaceutically acceptable salt thereof.
In an aspect, the present invention provides a compound of formula Ha,

wherein M is selected from the group consisting of hydrogen, lithium, sodium, potassium, ammonium and combination thereof. The compound of formula lla is useful in the preparation of Safinamide or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
DEFINITIONS
Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances.
As used herein, the term "salt" or "pharmaceutically acceptable salt" refers to those salts of the compounds formed by the process of the present invention which are safe and effective in human beings and that possess the desired biological activity. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free acid or base with a suitable base or acid. Examples of pharmaceutically acceptable

salts include, but are not limited to: hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid, acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonicacid, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorsulfonate, citrate, formate, fumarate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesuifonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, representative alkali or alkaline earth metal salts such as sodium, lithium, potassium, calcium, magnesium, nontoxic ammonium/quaternary ammonium, and the like.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, the terms "comprising" and "comprises" mean the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended. The terms "about," "substantially" and the like are to be construed as modifying a term or value such that it is not an absolute, but does not read on the prior art. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by one skilled in the art. All ranges recited herein include the endpoints, including those that recite a range between two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
The term "optionally" is taken to mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.
Unless otherwise specified, the terms "pure" "purity", refer to a compound with 99% chemical purity or greater, as determined by methods conventional in art such as high performance liquid chromatography (HPLC) or other known methods. In general, this refers to purity with regard to undesired residual solvents, reaction by-products,

impurities, and unreacted starting materials. In some instances, the terms "pure" and "purity" may also include chiral purity or enantiomeric excess.
The term "compound" as used herein, refers to the compounds of this application, which includes the key starting materials, intermediates and/or the final product. Specifically, it refers to the compounds of formulae I, II, lla and/or III, isomers thereof, and pharmaceutically acceptable salts thereof.
The term "anti-solvent" refers to a solvent in which a compound is insoluble or less soluble or sparingly soluble.
Inventors of the present application have developed an improved, efficient and commercially viable process preparing Safinamide or a pharmaceutically acceptable salt thereof, in high yield and purity, which is devoid of the drawbacks of prior art.
In an aspect, the present invention provides a process for preparing Safinamide or a pharmaceutically acceptable salt thereof of formula I,

the process comprising:
a) contacting a reaction mixture comprising a compound of formula II and a suitable solvent,

with a bisulfite salt to form a compound of formula lla,


wherein M is selected from the group consisting of hydrogen, lithium, sodium, potassium, ammonium and combination thereof;
b) reacting the compound of formula lla with L-Alaninamide or a salt thereof in
presence of a base to obtain a compound of formula III; and

c) reducing the compound of formula III, with a reducing agent or by catalytic
reduction, to provide Safinamide or a pharmaceutically acceptable salt thereof.
The compound of formula II used in the reaction, some of which are known from the literature, may be obtained by methods known from the literature, or using methods known to one skilled in the art.
In certain embodiments, the compound of formula II used in the reaction may include:
i. direct use of a reaction mixture containing formula II compound that is obtained in the course of its synthesis and that comprises a suitable solvent, or by combining a solvent with the reaction mixture; or
ii. dissolving formula II compound in a solvent.
In embodiments of step a), suitable solvent used in the reaction is selected from the group consisting of: water, methanol, ethanol, 1-propanol, 2-propanol, tetrahydrofuran, dioxane, diethyl ether, methyl t-butyl ether, diisopropyl ether, butyl ether, diphenyl ether, methylphenyl ether, ethyl acetate, isopropyl acetate, acetone,

methyl ethyl ketone, methyl isobutyl ketone, toluene, xylenes, hexane, heptane, acetonitrile, propionitrile, butyronitrile, benzonitrile, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, sulfolane, dichloromethane, dichloroethane, and mixtures thereof.
In embodiments of step a), bisulfite salt used in the reaction is selected from the group consisting of lithium bisulfite, sodium bisulfite, potassium bisulfite and ammonium bisulfite.
In embodiments of step b), the compound of formula lla may be optionally treated with a base, prior to the reaction with L-Alaninamide or a salt thereof.
In embodiments of step b), base used in the reaction include organic or an inorganic base such as for example, diisopropylamine, dimethylamine, ethylenediamine, N,N-diisopropylmethylamine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, triethylamine, aniline, pyridine, piperidine, potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, potassium acetate, potassium methoxide, sodium hydride, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium acetate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, lithium carbonate, lithium hydrogen carbonate, lithium hydroxide, lithium acetate, lithium methoxide, barium hydroxide, calcium oxide; ammonia, ammonium chloride, and the like.
In embodiments of step c), the suitable reducing agent is selected from the group consisting of sodium borohydride, sodium cyanoborohydride, diisobuyl aluminum hydride, sodium bis (2-methoxyethoxy)aluminum hydride, triisobuyl aluminum, potassium diisobutyl-tert-butoxyaluminium hydride, lithium diisobutyl-tert-butoxyaluminium hydride, sodium diisobutyl- tert-butoxyaluminium hydride, diisobuyl aluminum butylated oxytoulene, sodium aluminum hydride, lithium aluminum hydride, bis(4- methyl-1 -piperazinyl) aluminum hydride and the like.
In embodiments of step c), compound of formula III may also be reduced by catalytic reduction. The catalytic reduction may be carried out with hydrogen gas in the presence of a heterogeneous catalyst in an organic solvent. The catalyst employed for the reduction is selected from nickel, rhodium, platinum and palladium.

In certain embodiments of step b) and step c), the reaction may be carried out in the presence of a solvent. Examples of solvents for this purpose include, but are not limited to, : water; alcohols, such as methanol, ethanol, 1 -propanol, 2- propanol, 1 -butanol, and 2-butanol; ethers, such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, cyclopropylmethyl ether, dioxane, and dimethoxyethane; esters, such as methyl acetate, ethyl formate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, and isobutyl acetate; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and diethyl ketone; nitriles, such as acetonitrile and propionitrile; amides, such as formamide, N,N-dimethylformamide, and N,N- dimethylacetamide; sulfoxides, such as dimethylsulfoxide; aliphatic and aromatic hydrocarbons such as n-pentane, isopentane, neopentane, n-hexane, isohexane, n- heptane, cyclohexane, methylcyclohexane, cycloheptane, petroleum ethers, benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, indane, naphthalene, tetralin, trimethylbenzene; halogenated hydrocarbons such as dichloromethane, 1 ,2- dichloroethane, trichloroethylene, chloroform, carbon tetrachloride; or mixtures of two or more thereof.
In certain embodiments, when Safinamide is obtained as a free base may be then transformed into desired salts according to known methods, in particular they are transformed into methanesulfonate salt.
In preferred embodiments, the pharmaceutically acceptable salt of Safinamide is methanesulfonate.
In an aspect, the present invention provides a compound of formula lla,

wherein M is selected from the group consisting of hydrogen, lithium, sodium, potassium, ammonium and combination thereof.
In an aspect, the present invention provides an isolated compound of formula lla,


wherein M is selected from the group consisting of hydrogen, lithium, sodium, potassium, ammonium and combination thereof. Preferably, M is sodium, hydrogen or combination thereof. The compound of formula Ila is useful in the preparation of Safinamide or a pharmaceutically acceptable salt thereof. The compound of formula lla may be isolated as crystalline or amorphous solid, preferably in crystalline form.
The chemical transformations described throughout the application may be carried out using substantially stoichiometric amounts of reactants, though certain reactions may benefit from using an excess of one or more of the reactants. Reactants, reagents, bases, solvents used herein can suitably be employed in an amount in a range of about 0.9 equivalent (e.g., at least about 1 equivalent) to 60 equivalents per equivalent of the other compound (substrate).
In various embodiments, the reaction is carried out at suitable temperatures less than about 150°C, less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, or any other suitable temperatures.
Compounds employed at various stages of the process described herein (formulae I, II, lla or III) can be prepared as a pharmaceutically acceptable salt by reacting the free acid or base form of the compound with a pharmaceutically acceptable inorganic or organic acid or base. The free acid or free base forms of the compounds of the invention can be prepared from the corresponding base addition salt or acid addition salt from, respectively. For example, a compound of the invention in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base. The completion of the reaction can be monitored by any suitable analytical technique.
The compounds at various stages of the processes including the final compound, of the present application may be isolated using conventional techniques known in the

art. For example, useful techniques include, but are not limited to, decantation, centrifugation, gravity filtration, suction filtration, concentrating, cooling, stirring, shaking, combining a solution with an anti-solvent, adding seed crystals, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, freeze-drying, and the like. The isolation may be optionally carried out at atmospheric pressure or under a reduced pressure. The solid that is obtained may carry a small proportion of occluded mother liquor containing a higher than desired percentage of impurities and, if desired, the solid may be washed with a solvent to wash out the mother liquor. Evaporation as used herein refers to distilling a solvent completely, or almost completely, at atmospheric pressure or under a reduced pressure. Flash evaporation as used herein refers to distilling of solvent using techniques including, but not limited to, tray drying, spray drying, fluidized bed drying, or thin-film drying, under atmospheric or a reduced pressure.
The compounds obtained by the chemical transformations at various steps described herein can be used for their following steps without further purification, or can be effectively separated and purified by employing a conventional method known to one skilled in the art, such as recrystallization, column chromatography, by transforming them into a salt form, or by washing with an organic solvent or with an aqueous solution, eventually adjusting the pH. The compounds obtained at various stages of the processes may be purified by precipitation or slurrying in suitable solvents, or by commonly known recrystallisation techniques. The suitable recrystallisation techniques include, but are not limited to, steps of concentrating, cooling, stirring, or shaking a solution containing the compound, combination of a solution containing a compound with an anti-solvent, seeding, removal/partial removal of the solvent, or combinations thereof, evaporation, flash evaporation, or the like. An anti-solvent as used herein refers to a liquid in which a compound is poorly soluble. Compounds can be subjected to any of the purification techniques more than one time, or can be subjected to more than one of the purification techniques, until the desired purity is attained.
Compounds of the processes described herein may also be purified by slurrying in suitable solvents, for example, by providing a compound in a suitable solvent, if required heating the mixture to higher temperatures, subsequently cooling, and recovering a compound having a higher purity. Optionally, precipitation or

crystallization at any of the steps described herein can be initiated by seeding of the reaction mixture with a small quantity of the desired product. Suitable solvents that can be employed for recrystallization or slurrying include, but are not limited to: alcohols, such as methanol, ethanol, 1 -propanol, sopropyl alcohol; ethers, such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, and dioxane; esters, such as methyl acetate, ethyl formate, ethyl acetate, isopropyl acetate; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and diethyl ketone; nitriles, such as acetonitrile and propionitrile; amides, such as formamide, N,N-dimethylformamide, and N,N-dimethylacetamide; sulfoxides, such as dimethyl sulfoxide; aliphatic and aromatic hydrocarbons, such as n-pentane, isopentane, hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, cyclohexane, cycloheptane, petroleum ethers, benzene, toluene, m-xylene, o-xylene, chlorobenzene and anisole; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride; water; or mixtures of two or more thereof.
In certain aspects of the present application, the purified Safinamide may be optionally washed with suitable solvent and dried under suitable drying conditions. Drying may be suitably carried out using equipment such as air tray dryer, vacuum tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like, at atmospheric pressure or under reduced pressure. The drying may be carried out at atmospheric pressure or under a reduced pressure at temperatures of less than about 150°C, or less than about 120°C, or less than about 100°C, or less than about 80°C, or less than about 65°C, or any other suitable temperature as long as Safinamide or a salt thereof is not degraded in quality. The drying may be carried out for any desired time until the required purity is achieved. For example, it may vary from about 1 to about 10 hours, or about 1 to 24 hours, or longer.
The dried product may optionally be subjected to a particle size reduction technique to obtain desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation sifting; milling using mills, such as, for example, ball, roller, or hammer mills, or jet mills, including, for example, air jet mills; or any other conventional technique. The desired particle sizes may also be achieved directly from the reaction mixture by

selecting equipment that is able to provide the compound with the desired particle sizes. Accordingly, Safinamide mesylate may have a desired particle size of less than about 200 μm, less than about 150 μm, less than about 100 μm, less than about 90 μm, less than about 80 μm, less than about 60 μm, less than about 50 μm, less than about 40 μm, less than about 30 μm, less than about 20 μm, less than about 10 μm or less than about 5 μm.
In another aspect, the present application provides Safinamide mesylate which is substantially free of process related impurities. In yet another aspect, Safinamide mesylate prepared according to the present invention has purity at least about 90%, at least about 95%, at least about 98% or at least about 99% by High-performance liquid chromatography (HPLC).
In yet another aspect, the present invention provides substantially pure Safinamide mesylate, which is 100% pure as determined using high performance liquid chromatography (HPLC).
In preferred embodiments, Safinamide or a pharmaceutically acceptable salt thereof, preferably Safinamide mesylate prepared according to the processes described herein are substantially pure, wherein the undesired impurities such as (S)-2-[3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)-benzylamino]propenamide, the respective R-enantiomer thereof, or the respective racemic mixture thereof, or pharmaceutically acceptable salts thereof, and 3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)benzaldehyde, stereoisomers thereof, or pharmaceutically acceptable salts thereof, are undetectable or below the limit of detection.
In certain aspects, Safinamide or a salt thereof can be conveniently prepared, or formed during the process of the invention, as solvates (e.g., hydrates). Hydrates can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture.
In certain aspects, Safinamide or a pharmaceutically acceptable salt thereof can conveniently be prepared in a desired solid-state form using techniques known in the art. The starting material, which can be used for the preparation of desired solid-state form, can be crude or pure Safinamide obtained by any method known in the art. The starting material for preparing a desired polymorphic form include crystalline forms, amorphous, or mixtures of amorphous and crystalline forms of Safinamide in any

proportions, obtained by any method. For example, amorphous form of Safinamide or a salt thereof can be obtained by, preparing a solution comprising Safinamide or a salt thereof, and isolating an amorphous form of Safinamide or a salt thereof. Isolation may be effected by removing the solvent, or by a precipitation technique. Suitable techniques which may be used for the removal of the solvent include using a rotational distillation device such as a Buchi RotavaporⓇ, spray drying, thin film drying, freeze drying (lyophilization), and the like, or any other suitable techniques. The solvent may be removed, optionally under reduced pressures, at temperatures less than about 100° C., less than about 75° C, less than about 60° C, less than about 50° C, or any other suitable temperatures. The choice of solvents, anti-solvents, methods of purification and isolation, is customary to one skilled in the art.
The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. Thus, for example, in each instance herein any of the terms "comprising" and "consisting of may be replaced with either of the terms. In addition, the solvents, temperatures, reaction durations, etc. delineated herein are for purposes of illustration only and one of ordinary skill in the art will recognize that variation of the reaction conditions can produce the desired products accordingly.
Certain specific aspects and embodiments of the present invention will be better understood in connection with the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner.
EXAMPLES
Example 1: Preparation of [[4-[(3-fluorophenyl)methoxy]phenyI]-hydroxy-methyljsulfonyloxysodium


Isopropyl alcohol (250 mL) was charged in to a round bottom flask at 25-30 °C, followed by 4-hydroxybenzaldehyde (25 g), potassium carbonate (34 g) and potassium iodide (3.4 g). The reaction mixture was stirred for 30 minutes at 25-30 °C. 3-fluorobenzyl chloride (35.5 g) was slowly added to the reaction mixture at 25-30 °C, then heated to 75-80 °C and maintained the reaction for 6 hours. The reaction mass was then cooled 25-30 °C and the undissolved solids were filtered and washed with isopropyl alcohol (25 mL). The mother liquor comprising 4-[(3-fluorophenyl)methoxy]benzaldehyde (formula II) compound was charged in a round bottom flask and to this a solution comprising sodium bisulfite (25.54 g) in water (50 mL) was added slowly at 25-30 °C and the reaction mixture was maintained for 2 hours at 25-30 °C. The solid thus obtained was collected by filtration, washed with isopropyl alcohol (50 mL) and water (100 mL) and dried under suction. The resultant solid was dried in oven under vacuum at 45-50 °C for 18 hours to obtain the title compound.
Yield: 67 g
Example 2: Preparation of Safinamide mesylate

Isopropyl alcohol (100 mL) and water (30 mL) was charged in to a round bottom flask at 25-30 °C. To this [[4-[(3-fluorophenyl)methoxy]phenyl]-hydroxy-methyl]sulfonyloxysodium (10 g) and potassium carbonate (10.33 g) was charged under stirring and the reaction was maintained for 2 hours at 25-30 °C. L-alaninamide hydrochloride (4.5 g) was charged in to the reaction mixture at 25-30 °C and maintained for 7 hours at 75-80°C. The reaction mixture was cooled to 0-5 °C, then sodium borohydride (1.13 g) was slowly added to it and was maintained for 1 hour at 25-30°C. The precipitated inorganic solid was filtered and washed with isopropyl alcohol (10 mL). Toluene (100 mL) was charged to the mother liquor, stirred for 30 minutes and the organic layer separated was concentrated under reduced pressure at 45-50 °C followed by isopropyl alcohol (20 mL) stripping. Isopropyl alcohol (50 mL) was added to the reaction mass, heated to 35-40 °C to obtain a clear solution and

methanesulfonic acid (2.87 g) was slowly added to it. The reaction mixture was cooled to 25-30°C and maintained for 2 hours. The solid thus obtained was collected by filtration and washed with isopropyl alcohol (10 mL). The resultant solid was dried in oven under vacuum at 45-50 °C for 15 hours to obtain the title compound.
Yield: 8.7 g
Example 3: Preparation of [[4-[(3-fluorophenyl)methoxy]phenyl]-hydroxy-methyl]sulfonyloxysodium

Isopropyl alcohol (500 mL) was charged in to a round bottom flask followed by 4-hydroxybenzaldehyde (50 g), potassium carbonate (67.9 g), potassium iodide (6.8 g) and 3-fluorobenzyl chloride (71 g) under stirring at 25-30 °C. Later the reaction mixture was heated to 75-85 °C and maintained for 4-6 hours. After completion of reaction, the reaction mixture was then cooled to 25-30 °C and the undissolved solids were filtered and washed with isopropyl alcohol (100 mL). The mother liquor comprising 4-[(3-fluorophenyl)methoxy]benzaldehyde (formula II) compound was charged in a round bottom flask and to this a solution comprising sodium bisulfite (51.1 g) in water (100 mL) was added at 25-30 °C and the reaction mixture was maintained for 2 hours at 25-30 °C. The solid thus obtained was collected by filtration, washed with isopropyl alcohol (100 mL) and dried under vacuum for 2 hours. The resultant solid was dried in oven under vacuum at 55-60 °C for 15 hours to obtain the title compound.
Yield: 135 g; Purity by HPLC: 99.60%
Example 4: Preparation of Safinamide free base


[[4-[(3-fluorophenyl)methoxy]phenyl]-hydroxy-methyl]sulfonyloxysodium (120 g) was charged in to a round bottom flask followed by water (1200 mL), saturated sodium bicarbonate solution (1200 mL) and toluene (1200 mL) at 25-30 °C. The reaction mixture was heated to 70-75 °C and maintained for 30 minutes. Later the reaction mixture was kept aside to settle down and layers were separated. The aqueous layer again extracted with toluene (600 mL), both the toluene layers were mixed together and washed with saturated sodium chloride solution (1200 mL) and water (1200 mL) at 30-35 °C. The final toluene layer was distilled off and the oily reaction mixture extracted was concentrated at 40-45 °C. The oily reaction mixture was then charged into autoclave reactor followed by methanol (840 mL), L-Alaninamide hydrochloride (103 g), triethylamine (151 mL) and 10% palladium carbon (1.20 g) at 25-30 °C. The reaction mixture in autoclave was purged with nitrogen followed by hydrogen, applied 4-8 kg of hydrogen pressure about 1 to 6 hours. After completion of reaction, reaction mixture was filtered through hyflo bed and washed with methanol (240 mL). The reaction mixture was charged into activated carbon (6 g) and stirred for 1 hour. The reaction mixture was again filtered through hyflo bed and washed with methanol (240 mL). The reaction mixture was completely distilled under vacuum at 45-50 °C. The water (1200 mL) was charged to reaction mixture and stirred for 1-3 hours. The desired compound was isolated by filtration, washed with water (240 mL) and dried under suction for 15-30 minutes to obtain crude compound (101.6 g).
The crude compound (101.6 g) was charged in to a round bottom flask followed by toluene (500 mL) under stirring at 25-30 °C. The reaction mixture was heated to 80-90 °C and stirred for 1 hour. The reaction mixture was cooled to 20-25 °C under stirring for 2 hours. The solid thus obtained was collected by filtration, washed with chilled toluene (200 mL) and dried under suction for 30 minutes. The resultant solid was dried in oven under vacuum at 45-50 °C for 15 hours to obtain the title compound.
Yield: 92 g; Purity by HPLC: 99.95%
Example 5: Preparation of Safinamide mesylate


Safinamide free base (80 g) was charged in to a round bottom flask followed by isopropyl alcohol (600 mL) under stirring at 25-30 °C, followed by slow addition of methane sulfonic acid (25.5 g) and isopropyl alcohol (200 mL) into the reaction mixture. The reaction mixture was heated to reflux temperature at 75-85 °C and maintained stirring for 1-2 hours at same temperature. The reaction mixture was then cooled to 25-30 °C and maintained for 1 hour. The solid thus obtained was collected by filtration, washed with isopropyl alcohol (160 ml_) and dried under suction for 30 minutes. The resultant solid was dried in oven under vacuum at 45-50 °C for 15 hours to obtain the title compound as white solid.
Yield: 102 g; Purity by HPLC: 99.9 %
Example 6: Purification of Safinamide mesylate
Safinamide mesylate (80 g) was charged in to a round bottom flask followed by water (800 mL) under stirring at 25-30 °C for 30 minutes. To adjust the pH of reaction mixture to basic the saturated sodium bicarbonate solution (600 mL) was added and maintained at 25-30 °C for 1 hour. The solid thus obtained was collected by filtration, washed with water (400 mL) and dried under suction for 30 minutes. The obtained solid was dried in oven under vacuum at 45-50 °C for 18 hours. The above dried solid was then charged in to a round bottom flask followed by isopropyl alcohol (800 mL), further slow addition of methane sulfonic acid (21.2 g) in to a reaction mixture under stirring at 25-30 °C. The reaction mixture was heated to reflux temperature at 75-85 °C and maintained stirring for 1 hour at same temperature. The reaction mixture was cooled to 25-30 °C and maintained for 2 hours. The solid thus obtained was collected by filtration, washed with isopropyl alcohol (160 mL) and dried under suction for 30 minutes. The resultant solid was dried in oven under vacuum at 45-50 °C for 15 hours to obtain the desired compound (76 g) as white solid.
The above compound (50 g) was charged in to a round bottom flask followed by isopropyl alcohol (500 mL) under stirring at 25-30 °C for 15 minutes. To adjust the pH

of reaction mixture to basic the saturated sodium bicarbonate solution (350 ml_) was added and maintained at 25-30 °C for 1 hour. The solid thus obtained was collected by filtration, washed with water (250 mL) and dried under suction for 30 minutes. The resultant solid was dried in oven under vacuum at 45-50 °C for 15 hours. The resultant solid was charged in to a round bottom flask followed by isopropyl alcohol (500 mL), further slow addition of methane sulfonic acid (13.6 g) in to the reaction mixture under stirring at 25-30 °C. The reaction mixture was heated to reflux temperature at 75-85 °C and maintained for 1 hour at same temperature. The reaction mixture was cooled to 25-30 °C and maintained stirring for 2 hours. The solid thus obtained was collected by filtration, washed with isopropyl alcohol (100 mL) and dried under suction for 30 minutes. The resultant solid was dried in oven under vacuum at 45-50 °C for 15 hours to obtain the title compound as white solid. The powder X-ray diffractogram (PXRD) of the obtained white solid is as illustrated in Figure 1.
Yield: 48.3 g; Purity by HPLC: 100 %

WE CLAIM:
1. A process for preparing Safinamide or a pharmaceutical^ acceptable salt thereof of formula I,

the process comprising:
a) contacting a reaction mixture comprising a compound of formula II and a
suitable solvent,

with a bisulfite salt to form a compound of formula lla,

wherein, M is selected from the group consisting of hydrogen, lithium, sodium, potassium, ammonium and combination thereof;
b) reacting the compound of formula lla with L-Alaninamide or a salt thereof in
presence of a base to obtain a compound of formula III; and


c) reducing the compound of formula III, with a reducing agent or by catalytic reduction, to provide Safinamide or a pharmaceutically acceptable salt thereof.
2. The process as claimed in claim 1, wherein the suitable solvent in step a) is selected from the group consisting of water, methanol, ethanol, 1-propanol, 2-propanol, tetrahydrofuran, dioxane, diethyl ether, methyl t-butyl ether, diisopropyl ether, butyl ether, diphenyl ether, methylphenyl ether, ethyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, hexane, heptane, acetonitrile, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, sulfolane, dichloromethane, dichloroethane, and mixtures thereof.
3. The process as claimed in claim 1, wherein the bisulfite salt used in step a) is selected from the group consisting of lithium bisulfite, sodium bisulfite, potassium bisulfite and ammonium bisulfite.
4. The process as claimed in claim 1, wherein the base in step b) is selected from the group consisting of diisopropylamine, dimethylamine, ethylenediamine, N,N-diisopropylmethylamine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, triethylamine, aniline, pyridine, piperidine, potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, potassium acetate, potassium methoxide, sodium hydride, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium acetate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, lithium carbonate, lithium hydrogen carbonate, lithium hydroxide, lithium acetate, lithium methoxide, barium hydroxide, calcium oxide; ammonia, and ammonium chloride.

5. The process as claimed in claim 1, wherein the compound of formula lla in step b), may be optionally treated with a base defined hereinabove, prior to the reaction with L-Alaninamide or a salt thereof.
6. The process as claimed in claim 1, wherein the reducing agent in step c) is selected from the group consisting of sodium borohydride, sodium cyanoborohydride, diisobuyl aluminum hydride, sodium bis (2-methoxyethoxy)aluminum hydride, triisobuyl aluminum, potassium diisobutyl-tert-butoxyaluminium hydride, lithium diisobutyl-tert-butoxyaluminium hydride, sodium diisobutyl- tert-butoxyaluminium hydride, diisobuyl aluminum butylated oxytoulene, sodium aluminum hydride, lithium aluminum hydride and bis(4- methyl-1 -piperazinyl) aluminum hydride.
7. The process as claimed in claim 1, wherein the catalytic reduction in step c) is carried out with hydrogen gas in the presence of a heterogeneous catalyst selected from nickel, rhodium, platinum and palladium.
8. The process as claimed in claim 1, the reaction in step b) and step c) may be carried out in the presence of a solvent selected from the group consisting of water, alcohol, ether, ester, nitrile, amide, hydrocarbons and mixtures thereof.
9. A compound of formula lla,

wherein M is selected from the group consisting of hydrogen, lithium, sodium, potassium, ammonium and combination thereof.
10. An isolated compound of formula lla,


wherein M is selected from the group consisting of hydrogen, lithium, sodium, potassium, ammonium and combination thereof, wherein the compound of formula lla is isolated as crystalline or amorphous solid.