Field of the invention:

The present invention relates to an improved process for the preparation of (R)-2-acetamido-N-benzyl-3-methoxypropionamide represented by the following structural formula-1,

(R)-2-acetamido-N-benzyl-3-methoxypropionamide is an anticonvulsant drug useful in the treatment of central nervous system disorders such as epilepsy and also useful in the treatment of diabetic neuropathy which is associated with diabetis mellitus. (R)-2-acetamido-N-benzyl-3-methoxypropionamide is marketed by UCB pharma under the brand name called VIMPAT®.

Background of the invention:

(R)-2-acetamido-N-benzyl-3-methoxypropionamide is commonly known as "Lacosamide" and its process for the preparation was first disclosed in US 5773475. Two different approaches for the preparation of Lacosamide have been reported in US 5773475. One of the disclosed process involves the reaction of D-serine with benzylchloroformate in presence of MgO/Ether to provide N-benzyloxycarbonyl-D-serine, which on further treatment with methyl iodide in the presence of silver oxide (Ag20) in acetonitrile to provide (R)-methyl 2-(benzyloxycarbonylamino)-3-methoxy propionate which on hydrolysis in presence of potassium carbonate in methanol to provide (R)-2-(benzyloxycarbonylamino)-3-methoxypropanoic acid. The so formed propanoic acid compound reacted with benzylamine in presence of isobutylchloroformate and N-methylmorpholine provides (R)-N-Benzyl-2-(benzyloxycarbonylamino)-3-methoxy propionamide. The deprotection of benzyloxy carbonyl (Cbz) group by using 10% Pd-C in methanol to provide (R)-N-Benzyl-2-amino-3-methoxypropionamide. N-acetylation of free amino compound by using acetic anhydride in the presence of pyridine in dry THF provides Lacosamide.

Tetrahedron asymmetry 1998, 9, 3841-3854 disclosed the another process for the preparation of Lacosamide. The disclosed process involves the reaction of D-serine with benzychloroformate and MgO in diethyl ether to provide N-benzyloxycarbonyl-D-serine, which on further treatment with benzylamine in presence of N-methylmorpholine and isobutylchloroformate in THF provides (R)-N-Benzyl-2-(benzyloxycarbonylamino)-3-hydroxypropionamide, thus obtained hydroxy intermediate was O-methylated by using methyl iodide in presence of Ag20 in acetonitrile to provide (R)-N-Benzyl-2-(benzyloxycarbonylamino)-3-methoxypropionamide. The deprotection of benzyloxy carbonyl(Cbz) group by using 10% Pd-C in methanol to provide (R)-N-benzyl-2-amino-3-methoxypropionamide. N-acetylation of free amino compound by using acetic anhydride in the presence of pyridine and DMAP in dry THF provides Lacosamide.

Advantages of the present Invention:

• Avoids the usage of costly reagents like silver oxide and methyl iodide, which are more expensive

• Avoids the usage of Pd/C catalyst for deprotection of N-protecting group

• Avoids the usage of MgO and ether solvent for the N-protection of D-serine

• Usage of simple and cost-effective methylating agents

• More economic and eco-friendly

Brief description of the Invention:

The first aspect of the present invention is to provide an improved process for the preparation of (R)-2-acetamido-N-benzyl-3-methoxypropionamide compound of formula-1, which comprises of the following steps:

a) Reacting the D-serine compound of formula-2 with benzylchloroformate in presence of a base and in a suitable solvent to provide N-benzyloxycarbonyl-D-serine compound of formula-3,

b) reacting the compound of formula-3 with benzylamine in presence of a base and a suitable reagent in a suitable solvent to provide (R)-N-benzyl-2-(benzyloxycarbonylamino)-3-hydroxypropionamide compound of formula-4,

c) deprotecting the benzyloxycarbonyl group from the compound of formula-4 with a suitable acid or its aqueous solution in the presence or absence of a suitable solvent to provide (R)-N-benzyl-2-amino-3 -hydroxy propanamide compound of formula-5,

d) reacting the compound of formula-5 with acetic anhydride in a suitable solvent to provide (R)-N-Benzyl-2-acetamido-3-hydroxypropanamide compound of formula-6,

e) O-methylating the compound of formula-6 with a suitable methylating agent in presence of a suitable base in a suitable solvent to provide (R)-2-acetamido-N-benzyl-3-methoxypropionamide compound of formula-1,

f) optionally purifying the compound obtained in step-(e) by using a suitable solvent to provide pure compound of formula-1.

The second aspect of the present invention is to provide an improved process for the preparation of (R)-N-benzyl-2-amino-3-hydroxypropanamide compound of formula-5, which comprises of reacting the (R)-N-benzyl-2-(benzyloxycarbonylamino)-3-hydroxypropionamide compound of formula-4 with a suitable acid or its aqueous solution in the presence or absence of a solvent.

The third aspect of the present invention is to provide an improved process for the preparation of (R)-2-acetamido-N-benzyl-3-methoxypropionamide compound of formula-1, which comprises of O-methylating the (R)-N-benzyl-2-acetamido-3-hydroxypropanamide compound of formula-6 with a suitable methylating agent in presence of a suitable base in a suitable solvent to provide the (R)-2-acetamido-N-benzyl-3 -methoxypropionamide compound of formula-1.

The fourth aspect of the present invention is to provide a one-pot process for the preparation of (R)-N-benzyl-2-acetamido-3-hydroxypropanamide compound of formula-6.

The fifth aspect of the present invention is to provide an improved process for the preparation of (R)-2-acetamido-N-benzyl-3-methoxypropionamide compound of

formula-1 from (R)-N-benzyl-2-acetamido-3-hydroxypropanamide compound of formula-6.
Detailed description of the Invention:

As used herein the present invention, the term "suitable solvent" refers to the solvent selected from "polar solvents" such as water; "polar aprotic solvents" such as dimethylsulfoxide, dimethylacetamide, dimethyl formamide and the like; "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like; "ether solvents" such as di-tert-butylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran and dimethoxyethane; "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like; "chloro solvents" such as methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform, chloro benzene and the like; "hydrocarbon solvents" such as benzene, toluene, xylene, heptane, hexane and cyclohexane; "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like; "esters solvents" such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like; and their mixtures thereof.

The term "base" herein the present invention is selected from inorganic bases selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide and the like; and the term "organic base" refers to the base selected from triethylamine, triethanolamine, isopropyl ethylamine, diisopropylethylamine, di-n-propylamine, N-methyl morpholine, piperidine, pyridine and the like;

As used herein the term "methylating agent" is selected from dimethyl sulfate, dimethyl carbonate, methyl iodide and methanesulfonyl chloride in presence of methanol.

The term "acid" herein the present invention is selected from hydrochloric acid, sulphuric acid and phosphoric acid or its aqueous solutions.

Unless otherwise specified, as used herein the present invention, the term "phase transfer catalyst" refers to reagents selected from the group consisting of but not limited to tetra butyl ammonium bromide (TBAB), tetrapropyl ammonium bromide, tributyl benzyl ammonium bromide, tetraoctyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide and ethyl triphenyl phosphonium bromide; or alkali iodides like sodium iodide, potassium iodide and lithium iodide.

The first aspect of the present invention is to provide an improved process for the preparation of (R)-2-acetamido-N-benzyl-3-methoxypropionamide compound of formula-1, which comprises of the following steps:

a) Reacting the D-serine compound of Formula-2,

with benzylchloroformate in presence of a suitable alkali metal bicarbonates or carbonates or hydroxide base in a suitable solvent selected from water, alcohol solvents, chloro solvents and hydrocarbon solvents or mixture thereof to provide the N-benzyloxy carbonyl-D-serine compound of formula-3,


b) reacting the compound of formula-3 with benzylamine in the presence of ethyl chloroformate or isobutyl chloroformate and N-methylmorpholine in a suitable solvent selected from water, alcohol solvents, chloro solvents and hydrocarbon solvents or mixture thereof to provide (R)-N-benzyl-2-N-(benzyloxy carbonylamino)-3 -hydroxy propionamide compound of formula-4,

c) deprotecting the benzyloxycarbonyl group from the compound of formula-4 with a suitable acid selected from hydrochloric acid, sulphuric acid or phosphoric acid with or without usage of a solvent selected from water, alcohol solvents, chloro solvents and hydrocarbon solvents or mixture thereof to provide (R)-N-benzyl-2- amino-3-hydroxypropionamide compound of formula-5,

d) reacting the compound of formula-5 with acetic anhydride in a suitable solvent selected from chloro solvents or ester solvents or protic solvents or mixture thereof to provide (R)-N-benzyl-2-acetamido-3-hydroxypropionamide compound of formula-6,

e) O-methylating the compound of formula-6, by treating it with suitable methylating agent selected from dimethylsulfate, dimethyl carbonate and methyl iodide in presence of a suitable base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tertiary butoxide, potassium tertiary butoxide and the like in a suitable solvent selected from ester solvents or chloro solvents or hydrocarbon solvents or water or mixture thereof to provide (R)-2-Acetamido-N-benzyl-3-methoxy propionamide compound of formula-1,

f) optionally purifying the compound obtained in step-(e) by dissolving in a suitable solvent selected from ester solvents or chloro solvents or hydrocarbon solvents or water or mixture thereof to provide pure compound of formula-1.

Wherein in step e) methanesulfonyl chloride in presence of methanol is also acting as a O-methylating agent in presence of a suitable base. The suitable base is selected from alkli metal hydroxides, alkali metal carbonates, alkali metal bicarbonates and alkali metal alkoxides.

In a preferred embodiment of the present invention to provide an improved process for the preparation of (R)-2-acetamido-N-benzyl-3-methoxypropionamide compound of formula-1, comprises of the following steps:

a) Reacting the D-serine compound of formula-2 with benzyl chloroformate in presence of sodium bicarbonate in water to provide the N-benzyloxycarbonyl-D-serine compound of formula-3,

b) reacting the compound of formula-3 with benzylamine in presence of ethyl chloroformate and N-methylmorpholine in methylene chloride to provide (R)-N-benzyl-2-N(benzyloxycarbonylamino)-3-hydroxypropionamide compound of formula-4,

c) reacting the compound of formula-4 with cone, hydrochloric acid to provide (R)-N-benzyl-2-amino-3-hydroxypropionamide compound of formula-5,

d) reacting the compound of formula-5 with acetic anhydride in water to provide (R)-N-benzyl-2-acetamido-3-hydroxypropionamide compound of formula-6,

e) O-methylating the compound of fomula-6 by treating with dimethylsulfate in presence of aqueous sodium hydroxide in water to provide (R)-2-Acetamido-N-benzyl-3-methoxypropionamide compound of formula-1,

f) optionally purifying the compound obtained in step-(e) by using ethyl acetate provides highly pure compound of formula-1.

The second aspect of the present invention is to provide an improved process for the preparation of (R)-N-benzyl-2-amino-3-hydroxypropanamide compound of formula-5, which comprises of the following steps:

a) Reacting the (R)-N-benzyl-2-(benzyloxycarbonylamino)-3-hydroxypropionamide compound of formula-4 with a suitable acid selected from hydrochloric acid, sulphuric acid, or phosphoric acid or its aqueous solutions,

b) heating the reaction mixture and stirring at 50°C,

c) cooling the reaction mixture to 20-25°C

d) washing the reaction mixture with chloro solvent,

e) cooling the reaction mixture to 0-10°C,

f) adjusting the pH of the reaction mixture in between 9 to 10 by using aqueous sodium hydroxide solution,

g) cooling the reaction mixture to 0-5°C,

h) filtering and drying the compound to get the compound of formula-5.

The obtained (R)-N-benzyl-2-amino-3-hydroxypropanamide compound of formula-5 as per the above aspect can be directly used in the next stage without isolation.

The third aspect of the present invention is to provide an improved process for the preparation of (R)-2-acetamido-N-benzyl-3-methoxypropionamide compound of formula-1, comprises of the following steps:

a) Reacting the (R)-N-benzyl-2-amino-3-hydroxypropionamide compound of formula-6 with a suitable methylating agent selected from methanesulfonyl chloride in presence of methanol, dimethylsulfate, dimethyl carbonate and methyl iodide in presence of a suitable base selected from organic or inorganic bases preferably alkali metal hydroxides in a suitable solvent,

b) stirring the reaction mixture at 5°C for 4hrs,

c) extracting the material with chloro solvents,

d) distilling the organic layer completely,

e) adding a ester solvents to the reaction mass,

f) heating the reaction mass to reflux temperature and stirring for 30 min,

g) filtering the obtained solid and washing with ester solvent,

h) cooling and stirring the reaction mass at 55-60°C for 4 hrs,

i) cooling and stirring the reaction mixture at 0-5 °C for 60 min,

j) filtering the solid and washing it with ester solvent,

k) adding the ester solvent to the obtained solid and refluxing for 30 min,

1) filtering and washing the obtained solid with ester solvent and dried to provide

(R)-2-acetamido-N-benzyl-3 -methoxypropionamide compound of formula-1.

The fourth aspect of the present invention provides a one-pot process for the preparation of (R)-N-benzyl-2-acetamido-3-hydroxypropanamide compound of formula-6, which comprises of reacting the (R)-N-benzyl-2-N-(benzyloxycarbonylamino)-3-hydroxypropionamide compound of formula-4 with suitable inorganic acid preferably conc .hydrochloric acid or its aqueous solution in the presence or absence of solvent to provide a solution of (R)-N-benzyl-2-amino-3-hydroxypropionamide compound of formula-5, which in-situ reacts with acetic anhydride to provide the compound of formula-6.

The fifth aspect of the present invention provides an improved process for the preparation of (R)-2-acetamido-N-benzyl-3-methoxypropionamide compound of formula-1, which comprises of methylating the (R)-N-benzyl-2-acetamido-3-hydroxy propanamide compound of formula-6 with a suitable methylating agent in presence of a base and in presence or absence of phase transfer catalyst in a suitable solvent to provide the compound of formula-1.

In a preferred embodiment, the process for the preparation of (R)-2-acetamido-N-benzyl-3-methoxypropionamide compound of formula-1, comprising of methylating the (R)-N-benzyl-2-acetamido-3-hydroxy propanamide compound of formula-6 with methanesulfonyl chloride in presence of methanol and sodium methoxide to provide the compound of formula-1.

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:
Example-1: Preparation of N-benzyloxycarbonyl-D-serine compound of formula-3.

Sodium bicarbonate (100 g) was added to a mixture of D-serine (50 g) and water (750ml) at 15-20°C. Benzylchloroformate (50 % solution in toluene)(194 g) was added slowly to the reaction mixture and stirred for 10 hours at 15-20°C. Filtered the reaction mixture and the filtrate was taken. The organic and aqueous layers were separated and washed the aqueous layer with methylene chloride. Aqueous layer pH was adjusted to 1.5 with hydrochloric acid (100 ml). Stirred the reaction mixture for 90 minutes. Filtered the solid and washed with water. Dried the material to get the title compound. Yield: 101 g

Example-2: Preparation of (R)-N-benzyl-2-N-(benzyloxycarbonylamino)-3-hydroxy propionamide compound of formula-4.

Ethylchloroformate (25 g) was slowly added to the pre-cooled mixture of N-benzyloxycarbonyl-D-serine (50 g) and methylene chloride (500 ml) at -30 to -20°C and stirred for 15 minutes. N-methylmorpholine (23.5 g) was slowly added at -30°C and stirred for 30min. Benzylamine (25 g) was added to the reaction mixture and stirred for 90 minutes at -30°C. The temperature of the reaction mixture was raised to 20-25°C and stirred for 60 minutes. Distilled off the solvent completely under reduced pressure at 40-45°C. Water (350 ml) was added to the reaction mixture and cooled the mass to 20°C and stirred for 60 min. Filtered the solid and washed with water (50 ml). Toluene (250 ml) was added to the wet material and heat the reaction mixture to around 110°C and distilled off the solvent and cool the reaction mass to 20°C and stirred for 60 min. Filtered the solid and again washed with toluene (50 ml). Dried the material to get the title compound. Yield: 58 g

Example-3: Preparation of (R)-N-benzyl-2-acetamido-3-hydroxypropionamide compound of formula-6.

A mixture of (R)-N-benzyl-2-N-(benzyloxycarbonylamino)-3-hydroxy propionamide (100 g) and concentrated hydrochloric acid (500 ml) was heated to 40-45°C and stirred for 7 hours. The reaction mixture was cooled to 20-25°C. After completion of the reaction the reaction mixture is washed with methylene chloride (200 ml) and cooled to 0-10°C. The pH of the reaction mixture is adjusted to 9 by using aqueous sodium hydroxide solution (160 g in 400 ml of water) and further cooled to 0-5°C. Acetic anhydride (62 g) was added to the reaction mixture at 0-5°C and stirred for 1 hr. Filtered the obtained solid and washed with water (100 ml) to get the title compound of formula-6.

Example-4: (R)-N-benzyl-2-acetamido-3-methoxypropionamide compound of formula-1.

To a solution of (R)-N-benzyl-2-acetamido-3-hydroxypropionamide (195 g wet compound) obtained as per example-3 in water (720 ml), di methyl sulfate (385 g) and sodium hydroxide solution (dissolve 120 g of sodium hydroxide in 120 ml water) was added over a period of 11 hr at 0-5°C and the reaction mixture was stirred for 3 hrs. After completion of the reaction the reaction mixture was extracted with methyl ne chloride (900 ml) and separated the organic layer and aqueous layer and the organic layer was washed with water (70 ml). The solvent from the reaction mixture was distilled off completely under atmospheric pressure to provide residue. Ethyl acetate (70 ml) was added to the obtained residue and distilled off the solvent at reduced pressure. Ethyl acetate (350 ml) was again added to the obtained residue and heated to reflux temperature and stirred for 30 min. Filtered the reaction mixture through hy flow bed and washed with ethyl acetate and cool the reaction mixture to 55-60°C and stirred for 4 hrs. The reaction mixture was further cooled to 0-5°C and stirred for 60 min. Filtered the obtained solid and washed with ethyl acetate. Ethyl acetate (350 ml) was added to wet solid and again refluxed for 30 min and cooled the reaction mass to 20-25°C and stirred for 60 min. Filtered the solid and washed with ethyl acetate (70 ml) and air dried the material to get the pure compound of formula-1.

Yield: 55 g

Example-5: (R)-N-benzyl-2-acetamido-3-methoxypropionamide compound of formula-1.
Sodium methoxide (1.2 g) was added to the solution of (R)-N-benzyl-2-acetamido-3-hydroxypropanamide compound of formula-6 (5 g) in methanol (50 ml), and the reaction mixture was cooled to 0-5°C. Methane sulfonyl chloride (6 g) was added slowly to the reaction mixture and then stirred for 12 hours at 0-5°C. Water was added to the reaction mixture. The reaction mixture was extracted with dichloromethane and washed with water. Distilled off the solvent completely from dichloromethane layer to get the title compound. Further the obtained compound was purified by column chromatography. Yield: 3.0 g

Example-6: (R)-N-benzyl-2-acetamido-3-methoxypropionamide compound of formula-1.

Sodium methoxide (1.6 g) was added to the solution of (R)-N-benzyl-2-acetamido-3-hydroxypropanamide compound of formula-6 (5 g) in methanol (50 ml), and the reaction mixture was cooled to 0-5°C. Methane sulfonyl chloride (6 g) was added slowly to the reaction mixture and then stirred for 12 hours at 0-5°C. Water was added to the reaction mixture. The reaction mixture was extracted with ethyl acetate and washed with water. Distilled off the solvent completely to get the title compound. Yield: 2.2 g

We Claim:

1. An improved process for the preparation of (R)-N-benzyl-2-amino-3-hydroxy
propionamide compound of formula-5,

which comprises of, reacting the (R)-N-benzyl-2-(benzyloxycarbonylamino)-3-hydroxypropionamide compound of formula-4, with a suitable inorganic acid or its aqueous solution in presence or absence of solvent to provide the compound of formula-5.

2. A process according to claim 1, wherein the inorganic acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid or its aqueous solutions, preferably hydrochloric acid and sulfuric acid and more preferably hydrochloric acid; and the solvent is selected from ester solvents, chloro solvents, hydrocarbon solvents, water or their mixtures thereof.

3. A process according to claim 1, wherein the reaction is carried out in the absence of solvent.

4. An improved process for the preparation of (R)-2-acetamido-N-benzyl-3-methoxy propionamide compound of formula-1, which comprises of the following steps:

a) Reacting the D-serine compound of formula-2,

with benzylchloroformate in presence of a suitable base selected from alkali metal carbonates, alkali metal bicarbonates and alkali metal hydroxides in a suitable polar solvent to provide N-benzyloxycarbonyl-D-serine compound of formula-3,

b) reacting the compound of formula-3 with benzylamine in presence of isobutylchloroformate or ethylchloroformate and N-methyl morpholine in a suitable solvent selected from polar aprotic solvents, ether solvents and chloro solvents or mixture thereof to provide (R)-N-benzyl-2-N-(benzyloxy carbonylamino)-3-hydroxypropionamide compound of formula-4,

Formula-4

c) deprotecting the benzyloxycarbonyl group from the compound of formula-4 with a suitable acid selected from hydrochloric acid, sulphuric acid or phosphoric acid with or without usage of solvents selected from alcohol solvents, chloro solvents, ester solvents and hydrocarbon solvents to provide (R)-N-benzyl-2-amino-3- hydroxypropionamide compound of formula-5,


d) reacting the compound of formula-5 with acetic anhydride in a suitable solvent selected from protic solvents, chloro solvents, ester solvents or hydrocarbon solvents or mixture thereof to provide (R)-N-benzyl-2-acetamido-3- hydroxypropionamide compound of formula-6,

e) O-methylating the compound of formula-6 with a suitable methylating agent selected from methanesulfonyl chloride in presence of methanol, dimethyl sulfate, dimethyl carbonate and methyl iodide in a suitable solvent selected from polar solvents, polar aprotic solvents, hydrocarbon solvents, ether solvents or mixture thereof in presence of a suitable base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and the like to provide (R)-2-acetamido-N-benzyl-3-methoxypropionamide compound of formula-1,

f) optionally purifying the compound obtained in step-(e) with a suitable solvent to provide pure compound of formula-1

5. An improved process for the preparation of (R)-2-acetamido-N-benzyl-3 methoxypropionamide compound of formula-1, comprises of the following steps:

a) Reacting the D-serine compound of formula-2 with benzylchloroformate in presence of sodium bicarbonate in water to provide N-benzyloxycarbonyl-D-serine compound of formula-3,

b) reacting the compound of formula-3 with benzylamine in presence of ethyl chloroformate and N-methyl morpholine in methylene chloride to provide the (R)-N-benzyl-2-N-(benzyloxycarbonylamino)-3 -hydroxypropionamide compound of formula-4,

c) treating the compound of formula-4 with concentrated hydrochloric acid to provide the (R)-N-benzyl-2-amino-3-hydroxypropionamide compound of formula-5,

d) reacting the compound of formula-5 with acetic anhydride in water to provide the (R)-N-benzyl-2-acetamido-3-hydroxypropionamide compound of formula-6,

e) O-methylating the compound of formula-6 with dimethyl sulfate in presence of aqueous sodium hydroxide in water to provide the (R)-2-acetamido-N-benzyl-3-methoxypropionamide compound of formula-1,

f) purifying the compound obtained in step-(e) by using ethyl acetate to provide the pure compound of formula-1.

6. An improved process for the preparation (R)-2-acetamido-N-benzyl-3-methoxypropionamide compound of formula-1,

which comprises of O-methylating the (R)-N-benzyl-2-acetamido-3-hydroxy propionamide compound of formula-6,

with a suitable methylating agent selected from methanesulfonyl chloride in presence of methanol, dimethyl sulfate, dimethyl carbonate and methyl iodide in presence of a suitable base selected from organic or inorganic bases preferably inorganic bases such as alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal alkoxides and the like in a suitable solvent selected from water, hydrocarbon solvents, ester solvents, alcohol solvents, ether solvents, chloro solvents, keto solvents and nitrile solvents or mixture thereof to provide (R)-2-acetamido-N-benzyl-3-methoxypropionamide compound of formula-1.

7. A process according to claim-6, wherein the methylating agent is dimethyl sulfate and the base is selected from alkali metal hydroxides, alkali metal alkoxides preferably sodium hydroxide and the solvent is selected from water, alcohol solvents and chloro solvents or mixture thereof, preferably water or alcohol solvents or mixture thereof, more preferably the selected solvent is water.

8. A process according to claim-6, wherein the reaction is carried out in the absence of a phase transfer catalyst.

9. An improved process for the preparation (R)-2-acetamido-N-benzyl-3-methoxypropionamide compound of formula-1, which comprises of reacting the (R)-N-benzyl-2-acetamido-3-hydroxypropionamide compound of formula-6 with methanesulfonyl chloride in presence of methanol and sodium methoxide.

10. One-pot process for the preparation of (R)-N-benzyl-2-acetamido-3-hydroxypropanamide compound of formula-6,

which comprises of reacting the (R)-N-benzyl-2-N-(benzyloxycarbonylamino)-3-hydroxypropionamide compound of formula-4,

with a suitable inorganic acid preferably hydrochloric acid in presence or absence of solvent to provide the solution of compound of formula-5,

which in-situ reacts with acetic anhydride in water to provide the compound of formula-6.