Field of the Invention:
The present invention relates to an improved process for the preparation of (R)-2-acetaniido-N-benzyl-3-methoxypropionamide. (R)-2-acetamido-N-benzyl-3-methoxypropionamide is commonly known as "Lacosamide" represented by the following structural formula-1

Lacosamide is an anticonvulsant drug useful in the treatment of central nervous system disorders such as epilepsy and also useful in the treatment of pain, particularly neuropathic pain such as diabetic neuropathic pain. Lacosamide is merkteted under brand name Vimpat®.
Background of the invention:
Lacosamide and process for its preparation has been disclosed in US 5773475. The disclosed process involves 0-methylation of (R)-2-acetamido-N-benzyl-3-hydroxy propanamide by reacting it with methyl iodide in presence of silver oxide in acetonitrile. The said process involves the usage of costly reagent like silver oxide and methyliodide for 0-methylation increases the cost of production and hence usage of the same in commercial scale is not possible. Moreover lacosamide obtained by the said process contaminated with more impurities. Hence there is a need in the art for the cost effective process preparation of pure lacosamide which involves the usage of simple and cost effective reagent.
The main aspect of the present invention is to provide a cost effective process for the preparation of lacosamide which avoids the problems associated with the prior art processes.

Brief Description of tlie Invention:
The first aspect of the present invention is to provide an improved process for the preparation of lacosamide compound of formula-1, which comprises of 0-methylating the (R)-2-acetamido-N-benzyl-3-hydroxypropanamide compound of formula-2 with suitable methylating agent in presence of a suitable aqueous base in a suitable solvent and in presence of a phase transfer catalyst provides the lacosamide compound of formula-1.
The second aspect of the present invention is to provide an improved process for the preparation of lacosamide compound of formula-1, which comprises of 0-methylating the (R)-2-acetamido-N-benzyl-3-hydroxypropanamide compoimd of formula-2 with suitable methylating agent in presence of a suitable base in a suitable solvent and in absence of a phase transfer catalyst provides the lacosamide compound of formula-1.
The third aspect of the present invention is to provide an improved process for the preparation of (R)-2-acetamido-N-benzyl-3-hydroxypropanamide compound of formula-2, which comprises of the following steps;
a) reacting the (R)-2-amino-3-hydroxypropanoic acid compound of formula-3 with aceticanhydride in presence of a suitable solvent provides (R)-2-acetamido-3-hydroxypropanoic acid compound of formula-4,
b) reacting the compoimd of fonnula-4 with benzylamine in presence of a base and activator in a suitable solvent provides the compound of formula-2.
The fourth aspect of the present invention is to provide a process for the purification of (R)-2-acetamido-N-benzyl-3-hydroxypropanamide compound of formula-2.
The fifth aspect of the present invention is to provide a process for the purification of lacosamide compound of formula-1.

Brief Description of drawings:
Figure-1: Illustrates the Powder X-ray diffractogram of lacosamide prepared as per the
process disclosed in example-2(b) of US 5773475
Detailed Description of the Invention:
Accordingly the present invention provides cost effective and improved industrial process for the preparation of lacosamide compoxmd of formula-1

As used herein the term "phase transfer catalyst" refers to the phase transfer catalyst selected from tetraethylammonium p-toluenesulfonate, tetrapropyl ammonium trifluoromethanesulfonate, tetraphenyl phosphonium hexafluoroantimonate, cetylpyridinium bromide, triphenylmethyl triphenyl phosponium chloride, benzyltriethyl ammonium chloride, benzyltrimethylammonium chloride, benzyltriphenylphosphonium chloride, benzytributylammonium chloride, butyl triethylammonium bromide, butyltriphenylphosphonium bromide, cetyltrimethyl ammonium bromide, cetyltrimethyl ammonium chloride, ethyltriphenylphosphonium bromide, ethyltriphenylphosphonium iodide, methyltrioctylammonium bromide, methyltriphenylphosphonium bromide, methyl triphenylphosphonium iodide, phenyl trimethylammonium chloride, tetrabutylammonium hydroxide, tetrabutyl ammonium perchlorate, tetrabutylammonium bromide, tetrabutyl ammonium hydrogensulphate, tetrabutylammonium iodide, tetrabutylammonium tetra fluoroborate, tetrabutyl ammonium thiocyanate, tetraethylammonium hydroxide, tetraethylammonium iodide, tetraethylammonium bromide, tetramethylammonium chloride, tetramethylammonium iodide, tetramethylammonium chloride, tetraoctyl ammonium bromide, tetraphenyl phosphonium bromide, tetrapropylammonium hydroxide, tetrapropylammonium bromide and tributylmethylammonium chloride.
As used herein the present invention the term "alcohol solvents" refers to methanol, ethanol, isopropanol, butanol, t-butaol; the term "ethers" refers to diethyl ether, diisopropylether, tetrahydrofuran and dimethoxyethane; the term "nitrile solvents" refers

to acetonitrile, propionitrile, butyronitrile and isobutyronitrile; the term "chloro solvents" refers to methylene chloride, dichloroethane, chloroform, carbontetrachloride and chlorobenzene; the term "hydrocarbon solvents" refers to benzene, toluene, xylene, heptane, hexane and cyclohexane; the term "polar aprotic solvents" refers to dimethylsulfoxide, dimethylacetamide and dimethyl formamide; "keto solvents" refers to acetone and methyl isobutyl ketone;
As used herein the term "inorganic base" refers to base selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate and bicarbonates such as sodiumbicarbonate and potassiumbicarbonate; alkali metal oxides such as sodium methoxide, potassium methoxide, sodiumtertiary butoxide, potassium tertiary butoxide or mixtures thereof;
As used herein the term "organic base" refers to the base selected from triethylamine, triethanolamine, diisopropylethylamine, di-n-propylamine or mixtures thereof;
The first aspect of the present invention provides an improved process for the preparation of lacosamide compoimd of formula-1, which comprises of 0-methylating the (R)-2-acetamido-N-benzyl-3-hydroxypropanamide compound of formula-2

with suitable methylating agent like dimethyl sulfate in presence of a suitable aqueous base in a suitable solvent and in presence of a phase transfer catalyst to provide the lacosamide compound of formula-1.
Wherein the suitable base used is selected from either inorganic or organic bases, preferably inorganic base such as alkali metal hydroxides. And the suitable solvent used is selected from hydrocarbon solvents, ester solvents, polar aprotic solvent, ether solvent.

nitrile solvents, chloro solvent, keto solvents or mixtures thereof, preferably hydrocarbon solvents.
In a preferred embodiment, the process for the preparation of lacosamide compound of formula-1 comprises of 0-methylating the (R)-2-acetamido-N-benzyl-3-hydroxypropanamide compound of formula-2

with dimethyl sulfate in presence of aqueous sodium hydroxide and tetrabutyalammonium bromide in toluene to provide the lacosamide compound of formula-1.
The second aspect of the present invention provides an improved process for the preparation of lacosamide compound of formula-1, which comprises of 0-methylating the (R)-2-acetamido-N-benzyl-3-hydroxypropanamide compound of formula-2

with suitable methylating agent like dimethyl sulfate in presence of a base in a suitable solvent and in the absence of a phase transfer catalyst to provide the lacosamide compound of formula-1.
The base used in the present invention is selected from inorganic or organic bases, preferably alkali metal hydroxide such as sodium hydroxide. And the suitable solvent used is selected from hydrocarbon solvents, ester solvents, polar aprotic solvent, ether solvent, nitrile solvents, chloro solvent, keto solvents or mixtures thereof, preferably hydrocarbon solvents.

The third aspect of the present invention provides an improved process for the preparation of (R)-2-acetamido-N-benzyl-3-hydroxypropanamidecompound of formula-2,

which comprises of
a) reacting the (R)-2-amino-3-hydroxypropanoic acid compound of formula-3

with acetic anhydride in presence of a suitable solvent like acetic acid provides (R)-2-acetamido-3-hydroxypropanoic acid compound of formula-4,

)) reacting the compound of formula-4 with benzylamine in presence of a suitable base
selected from triethylamine, triethanolamine, di-n-propylamine,
diisopropylethylamine and 4-methylmorpholine, preferably 4-methylmorpholine and a activator selected from alkylchloroformate such as isobutyl chloroformate in a suitable solvent selected from ether solvents like tetrahydrofuran or methyl tertiary butyl ether; chloro solvents like methylene chloride or ethylene chloride or mixtures thereof, to provide the compound of formula-2.
The fourth aspect of the present invention provides a process for the purification of (R)-2-acetamido-N-ben2yI-3-hydroxypropanamide compound of formula-2, which comprises of the following steps;

(a) dissolving/suspending the (R)-2-acetamido-N-benzyl-3-hydroxypropanamide compound of formula-2 in a suitable solvent selected from chloro solvents, ether solvents, alcohol solvents, ester solvents, nitrile solvents, keto solvents, hydrocarbon solvents, water or mixtures thereof,
(b) stirring the reaction mixture,
(c) filtering the solid and washing with suitable solvent,
(d) drying the solid to get the piire compoimd of formula-2.
In a preferred embodiment, the process for the purification of (R)-2-acetamido-N-benzyl-3-hydroxypropanamide compound of formula-2 comprises of the following steps;
(a) dissolving/suspending the (R)-2-acetamido-N-benzyl-3-hydroxypropanamide compound of fonnula-2 in a mixture of methylene chloride and methyl tertiarybutyl ether,
(b) stirring the reaction mixture for an hour at 25-35°C,
(c) filtering the precipitated solid and washing with methyl tertiarybutyl ether,
(d) drying the solid to get the pure compound of formula-2.
The fifth aspect of the present invention provides a process for the purification of lacosamide compound of formula-1, which comprises of the following steps,
(a) dissolving/suspending the lacosamide compound of formula-1 in a suitable solvent selected from chloro solvents, nitrile solvents, ether solvents, alcohol solvents, ester solvents, keto solvents, hydrocarbon solvents and water or mixtures thereof,
(b) stirring the reaction mixture,
(c) cooling the reaction mixture and stirring,
(d) filtering the solid and washing with suitable solvent,
(e) drying the solid to get the pure compound of formula-1.
In a preferred embodiment, the process for the purification of lacosamide compound of formula-1 comprises of the following steps;
(a) suspending the lacosamide compound of formula-1 in ethyl acetate,
(b) stirring the reaction mixture for an hour at 25-35°C,
(c) cooling the reaction mixture to 0-5°C and stirring for 1 hour.

(d) filtering the solid and washing with chilled ethyl acetate,
(e) drying the solid to get the pure lacosamide compound of formula-1.
The process disclosed in example-2(b) of US 5773475 for the preparation of lacosamide was repeated in the laboratory and the obtained solid was analyzed by Powder X-ray diffractogram. Thus obtained PXRD of crystalline lacosamide is represented in figure-1.
Further lacosamide obtained as per the present invention is further micronized or milled to get the desire particle size.
As used herein the term "pure" refers to the compound having purity greater than 98.00%, preferably greater than 99.00% and more preferably greater than 99.50% by HPLC.
XRD analysis of lacosamide was carried out using SIEMENS/D-5000 X-Ray diffractometer using Cu, Ka radiation of wavelength 1.54 A° and continuous scan speed of0.0457min.
Related substances of the lacosamide and intermediate compounds were analyzed by HPLC using the following conditions:
Apparatus: A liquid chromatograph is equipped with variable wavelength UV-detector. Column: X-bridge Cig 150 x 4.6 mm, 5 ^im or equivalent; Flow rate: 1.0 ml/min; Wavelength: 210 nm; Temperature: 25°C; Injection volimie 20 jiL; Run time 40 min; Elution: isocratic; and using acetonitrile and buffer in 85:15 v/v ratio as a mobile phase. Buffer is aqueous solution of sodium phosphate dihydrate.
The present invention is schematically represented as follows

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
ExampIe-1: Preparation of lacosamide compound of formula-1:
To a solution of (R)-2-acetamido-N-benzyl-3-hydroxypropanamide (15 grams) in toluene (150 ml), teterabutylammonium bromide (0.82 grams) was added and cooled to 5-10°C. Aqueous sodixmi hydroxide (15 ml) was added to it and stirred for 30 minutes. Dimethyl sulfate (24.27 ml) was added to the reaction mixture slowly and stirred for 30 minutes. Aqueous sodium hydroxide (23.4 ml) was added to the reaction mixture and stirred upto completion the reaction at 5-10°C. The reaction mixture was quenched with water and the aqueous layer was separated. Aqueous layer was acidified with citric acid and extracted into methylene chloride. The methylene chloride layer dried with sodium sulphate and distilled off completely to get the title compound as a solid. Yield: 5 grams
Example-2: Purification of Lacosamide compound of formula-1:
Ethyl acetate (25 ml) was added to Lacosamide obtained in example-1 and stirring the reaction mixture for an hour at 25-35°C. The reaction mixture was cooled to 0-5°C and stirred for an hour. The solid was filtered, washed with ethyl acetate and dried to get high pure compound of formula-1. The PXRD of obtained solid was similar to the PXRD represented in figure-1. Yield: 3.5 grams Purity by HPLC: 99.58%
Example-3: Purification of Lacosamide compound of formula-1:
The title compound was purified in a similar manner to example-3 except that a mixture of ethyl acetate (20 ml) and isopropyl acetate (5 ml) is used in place of ethyl acetate.
Yield: 3.6 grams Purity by HPLC: 99.61%

ExampIe-4: Preparation of (R)-2-acetainido-N-benzyI-3-hydroxypropanainide of formula-2:
4-methylmorpholine (7.3 ml) followed by isobutylchloroformate (12.35 ml) was added to a suspension of (R)-2-acetamido-3-hydroxypropanoic acid (7 grams) in tetrahydrofuran (147 ml) at -78 to -75°C, benzylamine (10.4 ml) was added to it and the reaction mixture temperature was raised to 30-35°C then stirred for 30 minutes. The reaction mixture was filtered and the filtrate was distilled off under reduced pressure. The obtained residue was dissolved in methylene chloride (35 ml) and washed with aqueous hydrochloric acid followed by sodium carbonate and then with water. The solvent fi-om the methylene chloride layer was distilled off completely under reduced pressure to get the title compound. Yield: 8 grams Purity by HPLC: 88.50%
£xample-5: Purification of (R)-2-acetamido-N-benzyl-3-hydroxypropanamide compound of formula-2:
The (R)-2-acetamido-N-benzyl-3-hydroxypropanamide compoiuid of formula-2 obtained in example-4 was dissolved in a mixture of methylene chloride (8 ml) and methyl tertiarybutyl ether (40 ml). The reaction mixture was stirred for an hour at 25-35°C. The obtained solid was filtered, washed with methyl tertiary butyl ether and then dried to the get the pure title compound. Yield: 5 grams Purity by HPLC: 98.20%
Example-6: Purification of (R)-2-acetamido-N-benzyl-3-hydroxypropanamide compound of formula-2:
The compoimd of fonnula-2 (4 grams) obtained in example-4 was dissolved in a mixture of chloroform (4 ml) and methyl tertiarybutyl ether (20 ml). The reaction mixture was stirred for an hour at 25-35°C. The obtained solid was filtered, washed v^dth methyl tertiary butyl ether and then dried to the get the pure title compound. Yield: 2.6 grams Purity by HPLC: 98.50%

Exmaple-7: Preparation of (R)-2-acetamido-3-hydroxyprDpanoic acid formuia-4:
Acetic anhydride (10.79 ml) was added to a suspension of D-serine(10 grams) in acetic acid (150 ml) and stirred at 25-35°C. After completion of the reaction, acetic acid was removed by distillation followed by co-distillation with tetrahydrofuran. Isopropyl alcohol (30 ml) and methyltertiarybutylether (60 ml) was added to the obtained residue and stirred for 30 minutes. The obtained solid was filtered off and then solvent from the filtrate was distilled off completely under reduced pressure to get the title compound. Yield: 15 grams

We Claim:
1. An improved cost effective industrial process for the preparation of lacosamide compound of formula-1,

which comprises of 0-methylating the (R)-2-acetamido-N-benzyl-3-hydroxypropanamide compoimd of formula-2

with suitable methylating agent like dimethyl sulfate in presence of a suitable aqueous base in a suitable solvent and in presence of a phase transfer catalyst provides the lacosamide compound of formula-1.
2. An improved cost effective industrial process for the preparation of lacosamide compound of formula-1,

which comprises of 0-methylating the (R)-2-acetamido-N-benzyl-3-hydroxy propanamide compound of formula-2


with suitable methylating agent like dimethyl sulfate in presence of a suitable base in a suitable solvent and in absence of a phase transfer catalyst provides the lacosamide compound of formula-1.
3. A process according to claim 1 & 2, wherein the base used is selected from inorganic
or organic base and the suitable solvent used is selected from hydrocarbon solvents,
ester solvents, polar aprotic solvent, ether solvent, nitrile solvents, chloro solvent,
keto solvents or mixtures thereof.
4, A process according to claim 1, wherein the phase transfer catalyst used is selected
from tetraethylammonium p-toluenesulfonate, tetrapropyl ammonium
trifluoromethanesulfonate, tetraphenyl phosphonium hexafluoroantimonate,
cetylpyridinium bromide, triphenylmethyl triphenyl phosponium chloride,
benzyltriethyl ammonium chloride, benzyltrimethylammonium chloride,
benzyltriphenylphosphonium chloride, benzytributylammonium chloride, butyl
triethylammonium bromide, butyltriphenylphosphonium bromide, cetyltrimethyl
ammonium bromide, cetylfrimethyl ammonium chloride, ethyltriphenylphosphonium
bromide, ethyltriphenylphosphonium iodide, methyltrioctylammonium bromide,
methyltriphenylphosphonium bromide, methyl triphenylphosphonium iodide, phenyl
trimethylammonium chloride, tetrabutylammonium hydroxide, tetrabutyl ammonium
perchlorate, tetrabutylammonium bromide, tetrabutyl ammonium hydrogensulphate,
tetrabutylammonium iodide, tetrabutylammonium tetra fluoroborate, tetrabutyl
ammonium thiocyanate, tetraethylammonium hydroxide, tetraethylammonium iodide,
tetraethylammonium bromide, tetramethylammonium chloride, tetramethyl
ammonium iodide, tetramethylammonium chloride, tetraoctyl ammonium bromide,
tetraphenylphosphonium bromide, tetrapropylammonium hydroxide, tetrapropyl
ammonium bromide and tributylmethylammonium chloride.

5. A process for the preparation of lacosamide compound of formula-1,

which comprises of 0-methylatiing the (R)-2-acetamido-N-benzyl-3-hydroxy propanamide compound of formula-2

with dimethyl sulfate in presence of aqueous sodium hydroxide solution and tetrabutylammonium bromide in toluene to provide the lacosamide compoimd of formula-1.
6. An improved process for the preparation of (R)-2-acetamido-N-benzyl-3-
hydroxypropanamide compound of formula-2,

which comprises of the following steps;
a) reacting the (R)-2-amino-3-hydroxypropanoic acid compound of formula-3

with acetic anhydride in presence of a suitable solvent provides the (R)-2-acetamido-3-hydroxypropanoic acid compound of fonnula-4,


b) reacting the compound of fomiula-4 with benzylamine in presence of a suitable base selected from triethylamine, triethanolamine, di-n-propylamine, diisopropylethylamine and 4-methylmorpholine and a activator selected from alkylchloroformate in a suitable solvent selected from ether solvent like tetrahydrofiiran or methyl tertiary butyl ether; chloro solvent selected from methyelene chloride or ethylene chloride or mixtures thereof, to provide the compound of formula-2.
7. A process for the purification of (R)-2-acetamido-N-ben2yl-3-hydroxypropanamide
compound of formula-2, which comprises of the following steps;
(a) dissolving/suspending the (R)-2-acetamido-N-benzyl-3-hydroxypropanamide compound of formula-2 in a suitable solvent selected from chloro solvents, ether solvents, alcohol solvents, ester solvents, nitrile solvents, keto solvents, hydrocarbon solvents, water or mixtures thereof,
(b) stirring the reaction mixture,
(c) filtering the solid and washing with suitable solvent,
(d) drying the solid to get the pure compound of formula-2.
8. A process for the purification of (R)-2-acetamido-N-benzyl-3-hydroxypropanamide
compound of formula-2 comprises of the following steps;
(a) Dissolving the (R)-2-acetamido-N-benzyl-3-hydroxypropanamide compoimd of formula-2 in a mixture of methylene chloride and methyl tertiarybutyl ether,
(b) stirring the reaction mixture for an hour at 25-35°C,
(c) filtering the precipitated solid and washing with methyl tertiarybutyl ether,
(d) drying the solid to get the pure compound of formula-2.

9. A process for the purification of lacosamide compound of formula-1, which
comprises of the following steps,
(a) dissolving/suspending the lacosamide compound of formula-1 in a suitable
solvent selected from chloro solvents, nitrile solvents, ether solvents, alcohol
solvents, ester solvents, keto solvents, hydrocarbon solvents and water or
mixtures thereof,
(b) stirring the reaction mixture,
(c) cooling the reaction mixture to 0-5 °C and stirring,
(d) filtering the solid and washing with suitable solvent,
(e) drying the solid to get the pure compound of formula-2.
10. A process for the purification of compound of formula-1, which comprises of the
following steps;
(a) suspending the lacosamide in ethyl acetate,
(b) stirring the reaction mixture for an hour at 25-35°C,
(c) cooling the reaction mixture to 0-5°C and stirring for an hour,
(d) filtering the solid and washing with chilled ethyl acetate,
(e) drying the solid to get the pure lacosamide compound of formula-1.