F O R M 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. – A PROCESS FOR PREPARING LACOSAMIDE USING NOVEL INTERMEDIATES
2. Applicant(s)

(a) NAME : LUPIN LIMITED
(b) NATIONALITY : An Indian Company
(c) ADDRESS : 159, CST Road, Kalina, Santacruz (East),
Mumbai – 400 098, State of Maharashtra
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed :

FIELD OF THE INVENTION
The present invention relates to a process for the preparation of (R)-2-acetamido-N-benzyl-3-methoxypropionamide i.e., Lacosamide. The present invention further relates to novel intermediates and their use in the preparation of Lacosamide.
BACKGROUND OF THE INVENTION
(R)-2-acetamido-N-benzyl-3-methoxypropionamide i.e., Lacosamide has the following chemical formula

Lacosamide is marketed under the trade name Vimpat® and is useful in the treatment of partial-onset seizures. It is also known to be useful for the treatment of neuropathic pain, migraine, osteoarthritis and fibromyalgia syndrome.
Lacosamide is broadly disclosed in US 5,654,301 (A) and specifically disclosed in US RE38,551 (E).
The process for the preparation of Lacosamide has been disclosed in US RE38,551 (E) and US 6,048,899 (A), which involves O-methylation step in presence of silver oxide. The above known processes have a number of disadvantage such as
(a) use of highly expensive reagent like silver oxide results in partial racemization which reduces the yield,
(b) use of MgO and ether solvent for N-protection of D-serine is not recommendable at commercial scale,
(c) requires column chromatography for purification of some of the intermediates and final compounds involved in the process; and hence difficult to carry out in commercial scale.
An alternative process for the preparation of Lacosamide is disclosed in WO 2006/037574 (A2) that involves O-methylation of the boc-protected amino acid in presence of either organo lithium reagent or a phase transfer catalyst. The organo lithium compounds are hazardous and expensive, and not recommendable at

commercial scale. The process also requires column chromatographic technique for purification of some of the intermediates involved in this process.
US 20090143471 (A1) discloses certain intermediates and methods of preparation of Lacosamide using the said intermediates, wherein very bulky trityl protecting group is used for N-protection of D-serine. Steric hindrance of bulky trityl protection affect O-methylation step, which reduces the yield that makes the process less effective from an economic point of view.
Also, different routes of synthesis for the preparation of lacosamide have been reported in patent applications like, US 20100240926 (A1), US 20120209022 (A1), WO 2011/092672 (A2), US 20120283466 (A2), WO 2011095995 (A2), WO 2011/099033 (A2), WO 2011/130615 (A2), WO 2011/144983 (A2), US 20120095251 (A2), WO 2012/001710 (A2) and WO 2012/014226 (A2).
In view of problems in commercialization of process for the preparation of Lacosamide, there is a need for simple, cost effective, commercially feasible, industrially scalable and environment-friendly process for the preparation of Lacosamide with high purity and yield without racemization.
The protecting groups play a crucial role in multi-step synthesis of molecules like Lacosamide which has variety of functional groups. It has now been discovered that the secondary butyl group is useful as a protecting group of the amino functionality as it can be easily introduced to a protected amino group under mild conditions, also the secondary butyl group is relatively stable to basic condition.
The object of the present invention is to provide novel intermediates of Lacosamide which are as industrially applicable for the efficient synthesis of Lacosamide.
Another object of the present invention is to provide use of the novel intermediates in the preparation of Lacosamide.
Yet another object of the present invention is to provide an industrially advantageous process for the preparation of Lacosamide in overall high yield and purity using novel intermediates that is cost effective, eco-friendly, commercially viable as well as reproducible on industrial scale.
SUMMARY OF THE INVENTION The present invention relates to a compound of formula (II)


or a pharmaceutically acceptable salt, polymorph, solvate, hydrate, stereoisomer thereof, wherein,
R1 is –OH or –OCH3 and
R2 is –OH or –NH-CH2-Ph. The present invention also relates to a use of compound of a formula (II)

or a pharmaceutically acceptable salt, polymorph, solvate, hydrate, stereoisomer thereof, wherein,
R1 is –OH or –OCH3 and
R2 is –OH or –NH-CH2-Ph for the preparation of Lacosamide of formula (I)

The present invention also relates to a process for the preparation of Lacosamide of formula (I)

comprising the steps of
(a) reacting D-serine of formula (III) with suitable N-protecting reagent to produce a compound of a formula (IV)


(b) condensing a compound of formula (IV) with benzyl amine in presence of base to produce a compound of formula (V)

(c) O-methylation of a compound of formula (V) in the presence of suitable methylating agent and base to produce a compound of formula (VI)

(d) deprotecting the compound of formula (VI) to produce a compound of formula (VII)

(e) acetylating the compound of formula (VII) to produce Lacosamide of formula (I).
Alternatively, the present invention also relates to a process for the preparation of Lacosamide of formula (I)


comprising the steps of
(a) reacting D-serine of formula (III) with suitable N-protecting reagent to produce a compound of formula (IV)

(b) O-methylation of a compound of formula (IV) in the presence of suitable methylating agent and base to produce a compound of formula (VIII)

(c) condensing a compound of formula (VIII) with benzyl amine in presence of base to produce a compound of formula (VI)

(d) deprotecting the compound of formula (VI) to produce a compound of formula (VII)

(e) acetylating the compound of formula (VII) to produce Lacosamide of formula (I).
DETAILED DESCRIPTION OF THE INVENTION


According to one aspect of the present invention, there is provided a compound of the formula (II):
or a pharmaceutically acceptable salt, polymorph, solvate, hydrate, stereoisomer thereof, wherein,
R1 is –OH or –OCH3 and
R2 is –OH or –NH-CH2-Ph. The embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified.
According to one embodiment, specifically provided are compounds of the formula (II) in which R1 is –OH.
According to another embodiment, specifically provided are compounds of the formula (II) in which R1 is –OMe.
According to yet another embodiment, specifically provided are compounds of the formula (II) in which R2 is –OH.
According to yet another embodiment, specifically provided are compounds of the formula (II) in which R2 is –NH-CH2-Ph.
According to yet another embodiment, specifically provided are compounds of the formula (II) in which both R1 and R2 are –OH.
According to yet another embodiment, specifically provided are compounds of the formula (II) in which R1 is –OH and R2 is –NH-CH2-Ph.
According to yet another embodiment, specifically provided are compounds of the formula (II) in which R1 is –OMe and R2 is –NH-CH2-Ph.
According to yet another embodiment, specifically provided are compounds of the formula (II) in which R1 is –OMe and R2 is –OH.
Below are representative compounds, which are illustrative in nature only and are not intended to limit the scope of the invention,
Sec-butyl ((R)-1-(benzylamino)-3-hydroxy-1-oxopropan-2-yl)carbamate,
Sec-butyl ((R)-1-(benzylamino)-3-methoxy-1-oxopropan-2-yl)carbamate

or a pharmaceutically acceptable salt, polymorph, solvate, hydrate, stereoisomer thereof.
In second aspect, the present invention relates to a use of compound of formula (II)

or a pharmaceutically acceptable salt, polymorph, solvate, hydrate, stereoisomer thereof, wherein,
R1 is –OH or –OCH3 and
R2 is –OH or –NH-CH2-Ph for the preparation of Lacosamide of formula (I)

In third aspect, the present invention relates to a process for the preparation of Lacosamide of formula (I)

comprising the steps of
(a) reacting D-serine of formula (III) with suitable N-protecting reagent to produce a compound of a formula (IV)


(b) condensing a compound of formula (IV) with benzyl amine in presence of base to produce a compound of formula (V)

(c) O-methylation of a compound of formula (V) in the presence of suitable methylating agent and base to produce a compound of formula (VI)

(d) deprotecting the compound of formula (VI) to produce a compound of formula (VII)

(e) acetylating the compound of formula (VII) to produce Lacosamide of formula (I).
The compound of formula (IV) of present aspect can be prepared in step (a) by reacting D-serine of formula (III) with N-protecting reagent in presence of base, in suitable solvent. Preferably, the N-protecting reagent is secondary butyl chloroformate. The said reaction is carried out at temperature from about -20 to 60 C.
The base used in step (a) can be any organic or inorganic base. The suitable base is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, triethyl amine, diisopropylethyl amine, diethyl amine, isopropyl amine, morpholine, N-methyl morpholine, pyridine, ammonia and the like or mixtures thereof.
The reaction of step (a) is carried out in suitable solvent selected from the group consisting of water, alcohols, amides, sulphoxides, pyrrolidones, ethers, hydrocarbons,

ketones, esters, nitriles or mixtures thereof. Examples of suitable solvent includes, but are not limited to water, methanol, ethanol, isopropanol, butanol, iso-butanol, ethyl acetate, methyl acetate, tertiary butyl acetate, isopropyl acetate, acetone, methyl isobutyl ketone, methyl ethyl ketone, diethyl ketone, dimethyl ketone, methyl isobutyl ketone, toluene, ethyl ether, methyl ether, diisopropylether, methyltertbutylether, dioxane, tetrahydrofuran, N,N-dimethylformamide, N-methyl acetamide, N,N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, 1,1-dichloroethane, dichloromethane, chloroform, acetonitrile, benzene, xylene or mixtures thereof.
In a preferred embodiment, the process for the preparation of compound of formula (IV) comprises treating D-serine with secondary butyl chloroformate in presence of sodium carbonate in water and isolating the compound of formula (IV) by methods known in the art.
The compound of formula (V) of present aspect can be prepared in step (b) by condensing a compound of formula (IV) with benzyl amine in presence of base, optionally in presence of carboxyl group activator in suitable solvent. The said condensation reaction is carried out at temperature from about -50 C to 60 C.
The base used in step (b) can be any organic or inorganic base. The suitable base is selected from the group consisting of triethyl amine, diisopropylethyl amine, diethyl amine, isopropyl amine, morpholine, N-methyl morpholine, pyridine, ammonia, 1,8-diazabicyclo[5.4.0] undec-7-ene, 1,4-diazabicyclo[2.2.2] octane, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, and the like or mixtures thereof.
The carbonyl group present in formula (IV) needs activation before the condensation. The carboxyl group activator or coupling agent may be selected from alkyl or aryl chloroformate such as methyl chloroformate, isobutyl chloroformate, pivolyl chloride, phenyl chloroformate or nitrophenyl chloroformate; (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP); azoles such as N,N'-dicyclohexylcarbodiimide (DCC); imides such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), 1,1-carbonyldiimidazole and the like or mixtures thereof.
The condensation reaction of step (b) is carried out in suitable solvent such as aliphatic alicyclic or aromatic solvent which is selected from the group consisting of alcohols, amides, sulphoxides, pyrrolidones, ethers, hydrocarbons, ketones, esters,

nitriles or mixtures thereof. Examples of suitable solvent includes but not limited to methanol, ethanol, isopropanol, butanol, iso-butanol, ethyl acetate, methyl acetate, tertiarybutyl acetate, iso-propyl acetate, acetone, methylisobutyl ketone, methylethyl ketone, diethyl ketone, dimethyl ketone, toluene, ethyl ether, methyl ether, diisopropylether, methyltertbutyl ether, dioxane, tetrahydrofuran, N,N-dimethylformamide, N-methyl acetamide, N,N-dimethylacetamide, dimethylsulphoxide, N-methylpyrrolidone 1,1-dichloroethane, dichloromethane, chloroform, carbon tetrachloride, acetonitrile, benzene, xylene or mixtures thereof.
Preferably step (b) is carried out in presence of N-methyl morpholine and isobutyl chloroformate in dichoromethane at -20 C to -40 C and isolating the compound of formula (V) by methods known in the art.
The compound of formula (VI) of present aspect can be prepared in step (c) by reacting compound of formula (V) with methylating reagent and base optionally in presence of catalyst in suitable solvent. The said methylation reaction is carried out at temperature from about -20 C to 60 C.
Examples of suitable methylating agent include, but are not limited to dimethyl sulphate; methyl iodide; methyl chloride; methyl bromide; methyl fluoride; trimethyl silyldiazomethane; methyl aryl sulphonates such as methyl toluenesulfonates; methyl alkylsulphonates such as trimethylphosphonate and methyl triflet.
The base used in step (c) can be any organic or inorganic base. Examples of base that are useful in the O-methylation include, but are not limited to hydroxides, carbonates, bicarbonates, oxides, carboxylates, or alkoxides of alkali or alkaline earth metals; primary, secondary or tertiary amines; metal hydrides and organo metallic compounds. Some examples of suitable bases are triethyl amine, diisopropylethyl amine, diethyl amine, isopropyl amine, morpholine, N-methyl morpholine, pyridine, ammonia, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium ethoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide, sodium hydride, organolithium compounds such as n-butyl lithium, n-methyl lithium, hexyl lithium, LDA, LHMDS, or phenyl lithium, organozinc compounds including organo zinc halide, organo aluminum compounds including organo aluminum halides, organo tin compounds including organo tin halides, organo magnesium compounds including organo magnesium halides (grignard compounds) and the like or mixtures thereof.

The O-methylation is optionally be performed in presence of catalyst. The
catalyst used for the O-methylation include, but are not limited to imidazole,
dimethylaminopyridine, pyridine and phase transfer catalyst or mixtures thereof. The
phase transfer catalyst used in this reaction may be a quarternized amine salt, or a
phosphonium salt. The quarternized amine salt may be selected from
tetraalkylammonium salts such as sulfate, chloride or bromide; benzyltrialkylammonium
halides, cetyltrialkylammonium halides; Tweens (polyoxyethylene sorbitan esters) such
as Tween®20, Tween®40, Tween®60, Tween®80, Tween®85 etc. The suitable phase
transfer catalyst which can be used at step (c) may include tetraethylammonium p-
toluenesulfonate, tetrapropylammonium trifluoromethanesulfonate,
tetraphenylphosphonium hexafluoroantimonate, ethylpyridinium bromide,
triphenylmethyl triphenylphosphonium chloride, benzyltriethylammonium chloride,
benzyltrimethylammonium chloride, benzyltributylammonium chloride, benzyl triphenyl
phosphonium chloride, butyltriethyl ammonium bromide, butyltiphenylphosphonium
bromide, cetyltrimethyl ammonium bromide, cetyltrimethyl ammonium chloride, ethyl
triphenylphosphonium bromide, ethyltriphenylphosphonium iodide, methyltrioctyl
ammonium bromide, methyltriphenylphosphonium bromide,
methyltriphenylphosphonium iodide, phenyltrimethylammonium chloride,
tetrabutylammonium hydroxide, tetrabutylammonium perchlorate, tetrabutylammonium
bromide, tetrabutylammonium hydrogensulphate, tetrabutylammonium iodide,
tetrabutylammonium tetrafluoroborate, tetrabutylammonium thiocyanate,
tetraethylammonium hydroxide, tetraethylammonium iodide, tetramethylammonium
chloride, tetraoctylammonium bromide, tetraphenylphosphonium bromide,
tetrapropylammonium hydroxide, tetrapropylammonium bromide and
tributylmethylammonium chloride.
The O-methylation reaction of step (c) is carried out in suitable solvent such as aliphatic, alicyclic or aromatic solvent which is selected from the group consisting of alcohols, amides, sulphoxides, pyrrolidones, ethers, hydrocarbons, ketones, esters, nitriles or mixtures thereof. Examples of suitable solvent include, but are not limited to methanol, ethanol, isopropanol, butanol, iso-butanol, ethyl acetate, methyl acetate, tertiary butyl acetate, isopropyl acetate, acetone, methyl isobutyl ketone, methyl ethyl ketone, diethyl ketone, dimethyl ketone, methyl isobutyl ketone, toluene, ethyl ether, methyl ether, diisopropylether, methyltertbutylether, dioxane, tetrahydrofuran, N,N-dimethylformamide, N-methyl acetamide, N,N-dimethylacetamide, dimethylsulphoxide,

N-methylpyrrolidone 1,1-dichloroethane, dichloromethane, chloroform, acetonitrile, benzene, xylene, monoglyme, diglyme, diethoxy methane or mixtures thereof.
In a preferred embodiment, the process for the preparation of compound of formula (VI) comprises treating compound of formula (V) with dimethyl sulphate in presence of sodium hydroxide and tetrabutylammonium bromide in dichloromethane at 0 C to 10 C and isolating the compound of formula (VI) by methods known in the art.
The compound of formula (VII) of present aspect can be prepared in step (d) by deprotecting the compound of formula (VI) in presence of suitable deprotecting agent. The said deprotection reaction is carried out at temperature from about -10 C to 100 C.
This reaction can be performed in presence of organic or inorganic acids. Strong as well as mild acidic conditions can be suitable for deprotection. The organic acid may be selected form carboxylic acid or sulphonic acid such as trifluoroacetic acid, trifluoromethane sulphonic acid, methane sulphonic acid, formic acid, tartaric acid and p-touenesulphonic acid. The inorganic acid may be selected from hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid and sodium hydrogen phosphate.
The deprotection reaction of step (d) is carried out in absence or presence of suitable organic solvent such as aliphatic, alicyclic or aromatic solvent which is selected from the group consisting of alcohols, amides, sulphoxides, pyrrolidones, ethers, hydrocarbons, ketones, esters, nitriles or mixtures thereof. Examples of suitable solvent includes but not limited to methanol, ethanol, isopropanol, butanol, iso-butanol, ethyl acetate, methyl acetate, tertiary butyl acetate, isopropyl acetate, acetone, methyl isobutyl ketone, methyl ethyl ketone, diethyl ketone, dimethyl ketone, methyl isobutyl ketone, toluene, ethyl ether, methyl ether, diisopropylether, methyltertbutylether, cyclopentyl methyl ether, dioxane, tetrahydrofuran, N,N-dimethylformamide, N-methyl acetamide, N,N-dimethylacetamide, dimethylsulphoxide, N-methylpyrrolidone 1,1-dichloroethane, dichloromethane, chloroform, carbon tetrachloride, acetonitrile, benzene, xylene, monoglyme, diglyme, diethoxy methane or mixtures thereof.
In a preferred embodiment, the process for the preparation of compound of formula (VII) comprises treating compound of formula (VI) with Conc. HCl at 65 C to 70 C and isolating the compound of formula (VII) by methods known in the art.
Step (e) involves acylation of free amino acid of formula (VII) to form Lacosamide of formula (I). The said reaction is carried out at temperature from about 0 to 80 C.

N-acetylation can be performed in presence of acetylating agent such as acetic anhydride, acetyl chloride, acetic acid and the like. The acetylation can be performed in the presence or absence of base.
The base used in step (e) can be any organic or inorganic base. Examples of base that are useful in the acetylation step include, but are not limited to hydroxides, carbonates, bicarbonates, oxides, carboxylates, or alkoxides of alkali or alkaline earth metals and primary, secondary or tertiary amines. Some examples of suitable bases are triethyl amine, diisopropylethyl amine, diethyl amine, isopropyl amine, morpholine, N-methyl morpholine, pyridine, ammonia, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium ethoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide and the like or mixtures thereof.
The N-acetylation reaction of step (e) is carried out in suitable solvent such as aliphatic, alicyclic or aromatic solvent which is selected from the group consisting of water, alcohols, amides, sulphoxides, pyrrolidones, ethers, hydrocarbons, ketones, esters, nitriles or mixtures thereof. Examples of suitable solvent includes but not limited to water, methanol, ethanol, isopropanol, butanol, iso-butanol, ethyl acetate, methyl acetate, tertiary butyl acetate, isopropyl acetate, acetone, methyl isobutyl ketone, methyl ethyl ketone, diethyl ketone, dimethyl ketone, methyl isobutyl ketone, toluene, ethyl ether, methyl ether, diisopropylether, methyltertbutylether, dioxane, tetrahydrofuran, N,N-dimethylformamide, N-methyl acetamide, N,N-dimethylacetamide, dimethylsulphoxide, N-methylpyrrolidone 1,1-dichloroethane, dichloromethane, chloroform, acetonitrile, benzene, xylene, monoglyme, diglyme, diethoxy methane or mixtures thereof.
In a preferred embodiment, the process for the preparation of compound of formula (I) comprises treating the compound of formula (VII) with acetyl chloride and sodium carbonate in dichloromethane at 25 C to 30 C and isolating the compound formula of (I) by methods known in the art.
Finally, Lacosamide can be isolated from the reaction mixture with improved purity by recrystallization in an appropriate solvent by using any suitable techniques. In a preferred embodiment, the process comprises dissolving crude Lacosamide in an appropriate solvent such as ethyl acetate at 70 C, precipitating Lacosamide by cooling the solution to about 0-5 C, and isolating crystalline Lacosamide.

In fourth aspect, the present invention relates to a process for the preparation of Lacosamide of formula (I)

comprising the steps of
(a) reacting D-serine of formula (III) with suitable N-protecting reagent to produce a compound of formula (IV)

(b) O-methylation of a compound of formula (IV) in the presence of suitable methylating agent and base to produce a compound of formula (VIII)

(c) condensing a compound of formula (VIII) with benzyl amine in presence of base to produce a compound of formula (VI)

(d) deprotecting the compound of formula (VI) to produce a compound of formula (VII)

(e) acetylating the compound of formula (VII) to produce Lacosamide of formula (I).
The compound of formula (IV) of present aspect can be prepared in step (a) by reacting D-serine of formula (III) with N-protecting reagent in presence of base, in suitable solvent. Preferably, the N-protecting reagent is secondary butyl chloroformate. The said reaction is carried out at temperature from about -20 to 60 C.
The base used in step (a) can be any organic or inorganic base. The suitable base is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, triethyl amine, diisopropylethyl amine, diethyl amine, isopropyl amine, morpholine, N-methyl morpholine, pyridine, ammonia and the like or mixtures thereof.
The reaction of step (a) is carried out in suitable solvent selected from the group consisting of water, alcohols, amides, sulphoxides, pyrrolidones, ethers, hydrocarbons, ketones, esters, nitriles or mixtures thereof. Examples of suitable solvent includes, but are not limited to water, methanol, ethanol, isopropanol, butanol, iso-butanol, ethyl acetate, methyl acetate, tertiary butyl acetate, isopropyl acetate, acetone, methyl isobutyl ketone, methyl ethyl ketone, diethyl ketone, dimethyl ketone, methyl isobutyl ketone, toluene, ethyl ether, methyl ether, diisopropylether, methyltertbutylether, dioxane, tetrahydrofuran, N,N-dimethylformamide, N-methyl acetamide, N,N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, 1,1-dichloroethane, dichloromethane, chloroform, acetonitrile, benzene, xylene or mixtures thereof.
The compound of formula (VIII) of present aspect can be prepared in step (b) by reacting compound of formula (IV) with methylating reagent and base optionally in presence of catalyst in suitable solvent. The said methylation reaction is carried out at temperature from about -20 to 60 C.
Examples of suitable methylating agent include, but are not limited to dimethyl sulphate; methyl iodide; methyl chloride; methyl bromide; methyl fluoride; trimethyl silyldiazomethane; methyl aryl sulphonates such as methyl toluenesulfonates; methyl alkylsulphonates such as trimethylphosphonate and methyl triflet.
The base used in step (b) can be any organic or inorganic base. Examples of base that are useful in the O-methylation include, but are not limited to hydroxides, carbonates, bicarbonates, oxides, carboxylates, or alkoxides of alkali or alkaline earth

metals; primary, secondary or tertiary amines; metal hydrides and organo metallic compounds or mixtures thereof. Some examples of suitable bases are triethyl amine, diisopropylethyl amine, diethyl amine, isopropyl amine, morpholine, N-methyl morpholine, pyridine, ammonia, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium ethoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide, sodium hydride, organolithium compounds such as n-butyl lithium, n-methyl lithium, hexyl lithium, LDA, LHMDS, or phenyl lithium, organozinc compounds including organo zinc halide, organo aluminum compounds including organo aluminum halides, organo tin compounds including organo tin halides, organo magnesium compounds including organo magnesium halides (grignard compounds) and the like.
The O-methylation is optionally be performed in presence of catalyst. The
catalyst used for the O-methylation includes, but are not limited to imidazole,
dimethylaminopyridine, pyridine and phase transfer catalyst or mixtures thereof. The
phase transfer catalyst used in this reaction may be a quarternized amine salt, or a
phosphonium salt. The quarternized amine salt may be selected from
tetraalkylammonium salts such as sulfate, chloride or bromide; benzyltrialkylammonium
halides, cetyltrialkylammonium halides; Tweens (polyoxyethylene sorbitan esters) such
as Tween®20, Tween®40, Tween®60, Tween®80, Tween®85 etc. The suitable phase
transfer catalyst which can be used at step (b) may include tetraethylammonium p-
toluenesulfonate, tetrapropylammonium trifluoromethanesulfonate,
tetraphenylphosphonium hexafluoroantimonate, ethylpyridinium bromide,
triphenylmethyl triphenylphosphonium chloride, benzyltriethylammonium chloride,
benzyltrimethylammonium chloride, benzyltributylammonium chloride, benzyl triphenyl
phosphonium chloride, butyltriethyl ammonium bromide, butyltiphenylphosphonium
bromide, cetyltrimethyl ammonium bromide, cetyltrimethyl ammonium chloride, ethyl
triphenylphosphonium bromide, ethyltriphenylphosphonium iodide, methyltrioctyl
ammonium bromide, methyltriphenylphosphonium bromide,
methyltriphenylphosphonium iodide, phenyltrimethylammonium chloride,
tetrabutylammonium hydroxide, tetrabutylammonium perchlorate, tetrabutylammonium
bromide, tetrabutylammonium hydrogensulphate, tetrabutylammonium iodide,
tetrabutylammonium tetrafluoroborate, tetrabutylammonium thiocyanate,
tetraethylammonium hydroxide, tetraethylammonium iodide, tetramethylammonium

chloride, tetraoctylammonium bromide, tetraphenylphosphonium bromide, tetrapropylammonium hydroxide, tetrapropylammonium bromide and tributylmethylammonium chloride.
The O-methylation reaction of step (b) is carried out in suitable solvent such as aliphatic, alicyclic or aromatic solvent which is selected from the group consisting of alcohols, amides, sulphoxides, pyrrolidones, ethers, hydrocarbons, ketones, esters, nitriles or mixtures thereof. Examples of suitable solvent include, but are not limited to methanol, ethanol, isopropanol, butanol, iso-butanol, ethyl acetate, methyl acetate, tertiary butyl acetate, isopropyl acetate, acetone, methyl isobutyl ketone, methyl ethyl ketone, diethyl ketone, dimethyl ketone, methyl isobutyl ketone, toluene, ethyl ether, methyl ether, diisopropylether, methyltertbutylether, dioxane, tetrahydrofuran, N,N-dimethylformamide, N-methyl acetamide, N,N-dimethylacetamide, dimethylsulphoxide, N-methylpyrrolidone 1,1-dichloroethane, dichloromethane, chloroform, acetonitrile, benzene, xylene, monoglyme, diglyme, diethoxy methane or mixtures thereof.
The compound of formula (VI) of present aspect can be prepared in step (c) by condensing a compound of formula (VIII) with benzyl amine in presence of base, optionally in presence of carboxyl group activator in suitable solvent. The said condensation reaction is carried out at temperature from about -50 to 60 C.
The base used in step (c) can be any organic or inorganic base. The suitable base is selected from triethyl amine, diisopropylethyl amine, diethyl amine, isopropyl amine, morpholine, N-methyl morpholine, pyridine, ammonia, 1,8-diazabicyclo[5.4.0] undec-7-ene, 1,4-diazabicyclo[2.2.2] octane, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, and the like or mixtures thereof.
The carbonyl group present in formula (VIII) needs activation before the condensation. The carboxyl group activator or coupling agent may be selected from alkyl or aryl chloroformate such as methyl chloroformate, Isobutyl chloroformate, pivolyl chloride, phenyl chloroformate or nitrophenyl chloroformate; (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP); azoles such as N,N'-dicyclohexylcarbodiimide (DCC); imides such as 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDC), 1,1-carbonyldiimidazole and the like.
The condensation reaction of step (c) is carried out in suitable solvent such as aliphatic alicyclic or aromatic solvent which is selected from the group consisting of

alcohols, amides, sulphoxides, pyrrolidones, ethers, hydrocarbons, ketones, esters, nitriles or mixtures thereof. Examples of suitable solvent includes but not limited to methanol, ethanol, isopropanol, butanol, iso-butanol, ethyl acetate, methyl acetate, tertiarybutyl acetate, iso-propyl acetate, acetone, methylisobutyl ketone, methylethyl ketone, diethyl ketone, dimethyl ketone, toluene, ethyl ether, methyl ether, diisopropylether, methyltertbutyl ether, dioxane, tetrahydrofuran, N,N-dimethylformamide, N-methyl acetamide, N,N-dimethylacetamide, dimethylsulphoxide, N-methylpyrrolidone 1,1-dichloroethane, dichloromethane, chloroform, carbon tetrachloride, acetonitrile, benzene, xylene or mixtures thereof.
The compound of formula (VII) of present aspect can be prepared in step (d) by deprotecting the compound of formula (VI) in presence of suitable deprotecting agent. The said deprotection reaction is carried out at temperature from about -10 to 100 C.
This reaction can be performed in presence of organic or inorganic acids. Strong as well as mild acidic conditions can be suitable for deprotection. The organic acid may be selected form carboxylic acid or sulphonic acid such as trifluoroacetic acid, trifluoromethane sulphonic acid, methane sulphonic acid, formic acid, tartaric acid and p-toluenesulphonic acid. The inorganic acid may be selected from hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid and sodium hydrogen phosphate.
The deprotection reaction of step (d) is carried out in absence or presence of suitable organic solvent such as aliphatic, alicyclic or aromatic solvent which is selected from the group consisting of alcohols, amides, sulphoxides, pyrrolidones, ethers, hydrocarbons, ketones, esters, nitriles or mixtures thereof. Examples of suitable solvent includes but not limited to methanol, ethanol, isopropanol, butanol, iso-butanol, ethyl acetate, methyl acetate, tertiary butyl acetate, isopropyl acetate, acetone, methyl isobutyl ketone, methyl ethyl ketone, diethyl ketone, dimethyl ketone, methyl isobutyl ketone, toluene, ethyl ether, methyl ether, diisopropylether, methyltertbutylether, cyclopentyl methyl ether, dioxane, tetrahydrofuran, N,N-dimethylformamide, N-methyl acetamide, N,N-dimethylacetamide, dimethylsulphoxide, N-methylpyrrolidone 1,1-dichloroethane, dichloromethane, chloroform, carbon tetrachloride, acetonitrile, benzene, xylene, monoglyme, diglyme, diethoxy methane or mixtures thereof.
Step (e) involves acylation of free amino acid of formula (VII) to form Lacosamide of formula (I). The said reaction is carried out at temperature from about 0 to 80 C. N-acetylation can be performed in presence of acetylating agent such as

acetic anhydride, acetyl chloride, acetic acid and the like. The acetylation can be performed in the presence or absence of base.
The base used in step (e) can be any organic or inorganic base. Examples of base that are useful in the acetylation step include, but are not limited to hydroxides, carbonates, bicarbonates, oxides, carboxylates, or alkoxides of alkali or alkaline earth metals and primary, secondary or tertiary amines or mixtures thereof. Some examples of suitable bases are triethyl amine, diisopropylethyl amine, diethyl amine, isopropyl amine, morpholine, N-methyl morpholine, pyridine, ammonia, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium ethoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide and the like.
The N-acetylation reaction of step (e) is carried out in suitable solvent such as aliphatic, alicyclic or aromatic solvent which is selected from the group consisting of water, alcohols, amides, sulphoxides, pyrrolidones, ethers, hydrocarbons, ketones, esters, nitriles or mixtures thereof. Examples of suitable solvent includes but not limited to water, methanol, ethanol, isopropanol, butanol, iso-butanol, ethyl acetate, methyl acetate, tertiary butyl acetate, isopropyl acetate, acetone, methyl isobutyl ketone, methyl ethyl ketone, diethyl ketone, dimethyl ketone, methyl isobutyl ketone, toluene, ethyl ether, methyl ether, diisopropylether, methyltertbutylether, dioxane, tetrahydrofuran, N,N-dimethylformamide, N-methyl acetamide, N,N-dimethylacetamide, dimethylsulphoxide, N-methylpyrrolidone 1,1-dichloroethane, dichloromethane, chloroform, acetonitrile, benzene, xylene, monoglyme, diglyme, diethoxy methane or mixtures thereof.
Finally, Lacosamide can be isolated from the reaction mixture with improved purity by recrystallization in an appropriate solvent by using any suitable techniques. In a preferred embodiment, the process comprises dissolving crude Lacosamide in an appropriate solvent such as ethyl acetate, precipitating Lacosamide by cooling the solution to about 0-5 C, and isolating crystalline Lacosamide.
General Methods of Preparation The compounds described herein, including compounds of general formulas (I)-(VIII) and specific examples are prepared using techniques known to one skilled in the art through the reaction sequences depicted in schemes 1 & 2.

Furthermore, in the following schemes, where specific acids, bases, reagents, coupling agents, solvents, etc. are mentioned, it is understood that other suitable acids, bases, reagents, coupling agents etc. may be used and are included within the scope of the present invention. Modifications to reaction conditions, for example, temperature, duration of the reaction or combinations thereof, are envisioned as part of the present invention. The compounds obtained by using the general reaction sequences may be of insufficient purity. These compounds can be purified by using any of the methods for purification of organic compounds known to persons skilled in the art, for example, crystallization using different solvents in suitable ratios.
The starting materials for the below reaction schemes are commercially available or can be prepared according to methods known to one skilled in the art or by methods disclosed herein. In general, intermediates and compounds of the present invention may be prepared through the reaction scheme as follows.

D Serine of formula (III) is protected with N-protecting reagent in the presence of suitable solvent to give a compound of formula (IV). The protected D-serine compound of formula (IV) is condensed with benzyl amine in presence of suitable base in suitable solvent to produce a compound of formula (V). O-methylation of compound of formula (V) with suitable methylating agent in presence of base to give a compound of formula (VI), which is then, deprotected using deprotecting reagent to produce a compound of formula (VII). Lacosamide of formula (I) is prepared by reacting free amine compound of formula (VII) with acetylating agent.
Synthetic scheme 2


D Serine of formula (III) is protected with N-protecting reagent in the presence of suitable solvent to give a compound of formula (IV). The protected D-serine compound of formula (IV) is treated with methylating agent in presence of suitable base and solvent to produce a compound of formula (VIII). A compound of formula (VIII) is condensed with benzyl amine in presence of suitable base in suitable solvent to produce a compound of formula (VI), which is then deprotected using deprotecting reagent to produce a compound of formula (VII). Lacosamide of formula (I) is prepared by reacting free amine compound of formula (VII) with acetylating agent.
Experimental
Unless otherwise stated, work-up includes distribution of the reaction mixture between an organic and aqueous phase, separation of layers and drying the organic layer over sodium sulphate, filtration and evaporation of the solvent. Purification, unless otherwise mentioned, refers to purification by crystallization from an appropriate solvent or mixture of solvents.
The starling materials used for the preparation intermediates and compounds of invention are commercially available.
Example 1 (R)-2-acetamido-N-benzyl-3-methoxypropionamide i.e., Lacosamide Step 1: Preparation of (2R)-2-((sec-butoxycarbonyl)amino)-3-hydroxypropanoic acid
Sodium carbonate was dissolved in water (500 mL) and resultant mixture was cooled at 0-10 °C. To this cooled mixture was added D-serine (100g, 0.95 moles)

followed by addition of Sec-Butyl chloroformate (155.7 g, 1.14 moles). The reaction mixture was stirred for 5-6 hours. After completion of the reaction, acidify the aqueous layer to pH 3.0-4.0 with conc. hydrochloric acid (~200 mL). The resultant mixture was charged with toluene (200 mL) and the organic and aqueous layers were separated. Aqueous layer pH was adjusted to 1.5-2.0 by conc. hydrochloric acid (~60 mL) and extracts the reaction mixture in to ethyl acetate. The organic and aqueous layers were separated. Again aqueous layer was extracted with ethyl acetate (200 mL). The combined organic layers were concentrated to get the title compound as oil (Weight: 182 g, yield: 94%). 1H NMR (CDCl3) δ (ppm) 4.71-4.72 (t, 1H), 4.40 (m, 1H), 4.04-4.06 (d, 2H), 3.76-3.92 (s, 1H), 1.46-1.60 (m, 2H), 1.19-1.27 (d, 3H), 0.87-0.93 (t, 3H); IR (neat): 3345, 1696 cm-1; MS (m/z): 206 (M+1).
Step 2: Preparation of sec-butyl ((R)-1-(benzylamino)-3-hydroxy-1-oxopropan-2-yl) carbamate
(2R)-2-((sec-butoxycarbonyl)amino)-3-hydroxypropanoic acid (100g, 0.48 moles) was dissolved in dichloromethane (300 mL). To this reaction mixture was added N-methyl morpholine (80 mL, 0.72 moles) and stirred the mixture until a clear solution is obtained. A mixture of isobutyl chloroformate (70 mL, 0.54 moles) in dichloromethane (100 mL) was added to this solution at -20 to -40°C and stirred the reaction mixture for 15 minute. A solution of benzyl amine (58.5 mL, 0.54 moles) in dichloromethane (100 mL) was added in stirred mixture at -20 to -40°C and stirred the mixture for 1 hour at -20 to -40°C. Water (300 mL) was added to the resultant reaction mixture and layers were separated. The organic layer was washed with 5% HCl solution (200 mL) and 8% sodium bicarbonate solution (200 mL) followed by water (200ml). The organic layer was concentrated under reduced pressure. Cyclohexane (500 mL) was added and concentrated under reduced pressure. To this residue was added methyl tert-butyl ether (800 ml) and stirred for 3 hours. Filter the resultant solid and spray wash with methyl tert-butyl ether (200 ml). The filtrate was dried at 50°C under reduced pressure to get title compound (Weight: 80 g, yield: 56 %). 1HNMR (CDCl3) δ (ppm) 7.23-7.32 (m, 5H), 4.43 (s, 3H), 4.04-4.06 (d, 2H), 3.76-3.92 (s, 1H), 1.46-1.60 (m, 2H), 1.19-1.27 (d, 3H), 0.87-0.93 (t, 3H); IR (KBr): 3367, 1684, 1659, 1645 cm-1; Mass (m/z): 295 (M+1).

Step 3: Preparation of sec-butyl ((R)-1-(benzylamino)-3-methoxy-1-oxopropan-2-yl)carbamate
Sec-butyl ((R)-1-(benzylamino)-3-hydroxy-1-oxopropan-2-yl)carbamate (100g, 0.34 moles) was dissolved in dichloromethane (500 mL) and mixture was cooled to 0-10°C. Sodium hydroxide solution (68 g, 1.70 moles in 300 mL water) followed by tetra butyl ammonium bromide (TBAB) (5 g, 5 % moles) was added to the reaction mixture at 0-10°C. Dimethyl sulphate (172 g 1.36 moles) was slowly added to the mixture at 5-10°C and mixture was stirred for 5-6 hours. After completion of reaction, the layers were separated. The organic layer was washed with water (200 mL) and concentrate to get title compound (Weight: 78 g, yield: 75%). 1HNMR (CDCl3) δ (ppm) 7.23-7.32 (m, 5H), 4.43 (s, 3H), 4.04-4.06 (d, 2H), 3.76-3.92 (s, 1H), 3.35 (s, 3H), 1.46-1.60 (m, 2H), 1.19-1.27 (d, 3H), 0.87-0.93 (t, 3H); IR (KBr): 3294, 1684, 1646, 1238 cm-1; Mass (m/z): 309 (M+1).
Step 4: (R)-2-amino-N-benzyl-3-methoxypropanamide
Sec-butyl ((R)-1-(benzylamino)-3-methoxy-1-oxopropan-2-yl)carbamate was dissolved in conc. HCl ( 400 mL, 4 volume with respect to SM) and mixture was heated for 2-4 hours at 65-70°C. After completion of reaction, the reaction mixture was cooled to room temperature and wash with dichloromethane (200 mL). The layers were separated. Aqueous layer pH was adjusted to 9-10 with 30% sodium hydroxide solution keeping temperature below 20°C. The aqueous layer was extracted with dichloromethane (250 mL x 2). The dichloromethane layer containing (R)-2-amino-N-benzyl-3-methoxypropanamide used directly in next step. 1HNMR (CDCl3) δ (ppm) 7.24-7.36 (m, 5H), 4.37-4.44 (s, 2H), 3.51-3.56 (m, 3H), 3.35 (s, 3H); IR (neat): 3294, 1684, 1646, 1238 cm-1; Mass (m/z): 209 (M+1).
Step 5: Preparation of Lacosamide
Sodium carbonate (72.1 g 0.68 moles in 500 mL water) was added to the DCM layer containing (R)-2-amino-N-benzyl-3-methoxypropanamide (100 g, 0.48 moles) obtained as per step 4 at 20-30° C and the reaction mixture was cooled to 15-20°C. Acetyl chloride (40.5 g, 0.515 moles) was slowly added to the mixture by maintaining temperature 15 -20°C. After complete addition, the reaction mixture was stirred at 25-30°C. The layers were separated. The organic layer was washed with water (200 mL) and concentrated to get residue. Ethyl acetate (600 mL) was added to the residue and

mixture was heated to 70°C to obtain clear solution. Allow the solid to crystallize by cooling room temperature then at 0-5 °C. The obtained solid was filtered and dried to get Lacosamide as a white colour solid (Weight: 41 g, Yield: 50 %). 1HNMR (CDCl3) δ (ppm) 7.21-7.32 (m, 5H), 4.53-4.56 (t, 1H), 4.41 (s, 2H), 3.58-3.72 (d, 2H), 3.36 (s, 3H), 2.02 (s, 3H); IR (KBr): 3290, 3027, 1638 cm-1; Mass (m/z): 251 (M+1).

WE CLAIM:
(1) A process for the preparation of Lacosamide of formula (I)

comprising the steps of
(a) reacting D-serine of formula (III) with suitable N-protecting reagent to produce a compound of a formula (IV)

(b) condensing a compound of formula (IV) with benzyl amine in presence of base to produce a compound of formula (V)

(c) O-methylation of a compound of formula (V) in the presence of suitable methylating agent and base to produce a compound of formula (VI)

(d) deprotecting the compound of formula (VI) to produce a compound of formula (VII)


(e) acetylating the compound of formula (VII) to produce Lacosamide of formula (I).
2. The process according to claim 1, wherein secondary butyl chloroformate is used in step (a) as N-protecting reagent in presence of base.
3. The process according to claim 1, wherein the base used in step (a) is organic or inorganic base selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, triethyl amine, diisopropylethyl amine, diethyl amine, isopropyl amine, morpholine, N-methyl morpholine, pyridine and ammonia or mixtures thereof.
4. The process according to claim 1, wherein condensation in step (b) is optionally carried out in presence of carboxyl group activator.
5. The process according to claim 4, wherein the activator of the carboxyl group used in step (b) is alkyl or aryl chloroformate selected from methyl chloroformate, isobutyl chloroformate, pivolyl chloride, phenyl chloroformate and nitrophenyl chloroformate; azoles selected from N,N'-dicyclohexylcarbodiimide (DCC); imides selected from 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) and 1,1-carbonyldiimidazole; (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP); or mixtures thereof.
6. The process according to claim 1, wherein the base used in step (b) is organic or
inorganic base selected from the group consisting of triethyl amine, diisopropylethyl
amine, diethyl amine, isopropyl amine, morpholine, N-methyl morpholine, pyridine,
ammonia, 1,8-diazabicyclo[5.4.0] undec-7-ene, 1,4-diazabicyclo[2.2.2] octane, sodium
hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, potassium

carbonate, potassium bicarbonate, sodium carbonate and sodium bicarbonate, or mixtures thereof.
7. The process according to claim 1, wherein the methylating agent used in step (c) is
selected from the group consisting of dimethyl sulphate; methyl iodide; methyl chloride;
methyl bromide; methyl fluoride; trimethyl silyldiazomethane; methyl aryl sulphonates
such as methyl toluenesulfonates; methyl alkylsulphonates such as
trimethylphosphonate and methyl triflet.
8. The process according to claim 1, wherein the base used in step (c) is organic or
inorganic base selected from the group consisting of hydroxides, carbonates,
bicarbonates, oxides, carboxylates, alkoxides of alkali or alkaline earth metals; primary,
secondary or tertiary amines; metal hydrides and organo metallic compounds or
mixtures thereof.
9. The process according to claim 1, wherein O-methylation in step (c) is optionally
performed in presence of catalyst selected from the group consisting of imidazole,
dimethylaminopyridine, pyridine and phase transfer catalyst or mixtures thereof.
10. The process according to claim 1, wherein deprotectiong agent used in step (d) is
organic or inorganic acids selected from the group consisting of trifluoroacetic acid,
trifluoromethane sulphonic acid, methane sulphonic acid, formic acid, tartaric acid, p-
touenesulphonic acid, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric
acid and sodium hydrogen phosphate.
11. The process according to claim 1, wherein N-acylation in step (e) is carried out in the presence or absence of base using acetylating agent selected from acetic anhydride, acetyl chloride and acetic acid.
12. The process according to claim 1, wherein base used in step (e) is organic or inorganic base selected from the group consisting of hydroxides, carbonates, bicarbonates, oxides, carboxylates, or alkoxides of alkali or alkaline earth metals and primary, secondary or tertiary amines or mixtures thereof.

13. The process according to claim 1, wherein all the reactions of step (a) to (e) are
carried out in the presence or absence of aliphatic, alicyclic or aromatic solvent which
is selected from the group consisting of water, alcohols, amides, sulphoxides,
pyrrolidones, ethers, hydrocarbons, ketones, esters and nitriles or mixtures thereof.
14. A compound of formula (II)

or a pharmaceutically acceptable salt, polymorph, solvate, hydrate, stereoisomer thereof, wherein,
R1 is –OH or –OCH3 and
R2 is –OH or –NH-CH2-Ph.
15. Use of compound of formula (II)

or a pharmaceutically acceptable salt, polymorph, solvate, hydrate, stereoisomer thereof, wherein,
R1 is –OH or –OCH3 and
R2 is –OH or –NH-CH2-Ph for the preparation of Lacosamide of formula (I)

16. A process for the preparation of Lacosamide of formula (I)


comprising the steps of
(a) reacting D-serine of formula (III) with suitable N-protecting reagent to produce a compound of formula (IV)

(b) O-methylation of a compound of formula (IV) in the presence of suitable methylating agent and base to produce a compound of formula (VIII)

(c) condensing a compound of formula (VIII) with benzyl amine in presence of base to produce a compound of formula (VI)


(d) deprotecting the compound of formula (VI) to produce a compound of formula (VII)

(e) acetylating the compound of formula (VII) to produce Lacosamide of formula (I).