FIELD OF THE INVENTION
The present invention relates to a process for the preparation of an isolated impurities of Lacosamide having the following structures.

Lacosamide is chemically known as (R)-2-acetamido-N-benzyl-3-methoxypropionamide,
marketed under the brand name VIMPAT® for the adjunctive treatment of partial-onset seizures
in adults. U.S. reissue Patent No. RE 38551 specifically discloses Lacosamide in R-configuration
and process for its preparation.
European pharmacopoeia discloses the process related impurities of Lacosamide and these
specified impurities are designated as A, B, C, D, E, F, G, H, I, J and K.
The control of pharmaceutical impurities in active pharmaceutical ingredient [API] is currently a
critical and challenging issue to the pharmaceutical industry. Impurities are the unwanted
chemicals associated with the active pharmaceutical ingredients or formulated APIs. The presence
of these unwanted impurities can have unwanted pharmacological or toxicological effects even

in small amounts. It may influence the efficacy and safety of the pharmaceutical products. The International Conference on Harmonization (ICH) has a workable guideline regarding the control of impurities. As on date, impurity profile has become essential as per various regulatory requirements.
National and international regulatory authorities required very low limits of identified and uncharacterized impurities before an active pharmaceutical ingredient product is commercialized. Like any synthetic compound, Lacosamide can contain extraneous impurities that can come from many sources. They may be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products.
Impurity profile describes the identified and unidentified impurities present in a new drug substance. Impurity profiling is the common name of a group of analytical activities, which is the detection, identification/structure elucidation and quantitative determination of organic and inorganic impurities as well as residual solvents in bulk drugs and pharmaceutical formulations. It helps identifying the impurity present in API by analytical technique or methods.
The synthesized impurities are used as an impurity standard for the development of a selective analytical method for its quantitation in drug substance and for the routine API approval in quality control.
However as on date, there is no processes were reported for the preparation of these impurities in the prior art. Henceforth, there is a need to develop an improved, cost-effective process for the preparation of Lacosamide impurities with high chiral purity on commercial scale.
SUMMARY OF THE INVENTION
In one aspect, the present invention relates to a process for the preparation of Lacosamide impurity-C [(2E)-N-benzyl-3-methoxy-2-(N-methylacetamido)-propanamide]


which comprises:
a) reaction of compound of formula-II

with 40 % aqueous methylamine solution in dimethylformamide to give compound of formula-III;

b) N-acylation of compound of formula-III with acetic anhydride in presence of
triethylamine to obtain Lacosamide impurity-C.
In another aspect, the present invention provides a process for the preparation of Lacosamide impurity-K [2-acetamido-N-benzylprop-2-enamide]

which comprises:
a) treatment of compound of formula-IV


with aqueous sodium hydroxide solution to obtain Lacosamide impurity-K.
In another aspect, the present invention provides a process for the preparation of Lacosamide impurity-H [(2E)-2-acetamido-N-[(2E)-1-(benzylamino)-3-methoxy-1-oxopropan-2-yl]-3-methoxypropanamide]

which comprises:
a) reaction of compound of formula-V

with Di-tert-butyl dicarbonate in presence of sodium hydroxide to give compound of formula-VI;


b) methylation of compound of formula-VI with methyl iodide in presence of sodium
hydroxide to give compound of formula-VII;

c) condensation of compound of formula-VII with compound of formula-VIII

in presence of hydroxy benzotriazole and 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride followed by deprotecting hydrochloric acid to give compound of formula-IX;


d) N-acylation of compound of formula-IX with acetic anhydride to obtain Lacosamide impurity-H.
In another aspect, the present invention provides a process for the preparation of Lacosamide impurity-I [(2E)-N-benzyl-2-[(benzylcarbamoyl)amino]-3-methoxypropanamide]

which comprises:
a) treatment of compound of formula-X

with methanolic hydrochloric acid to give compound of formula-XI;

b) condensation of compound of formula-XI with isocyanatomethylbenzene in presence of
triethylamine to obtain Lacosamide impurity-I.

DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides a process for the preparation of Lacosamide impurities
Scheme-I illustrates the process for the preparation of Lacosamide impurity-C.

In step-1, compound of formula-(II) is reacted with 40 % aqueous methylamine solution in a suitable organic solvent followed by heating the resulting reaction mixture to give compound of formula-III as a pale yellow liquid.
The suitable solvent used in the reaction is selected from polar aprotic solvents like N,N-Dimethyl formamide, Dimethyl sulfoxide and preferably using N,N-Dimethyl formamide.
In step-2, subjecting the obtained compound of formula-III is acetylated with acetic anhydride in presence of a suitable base to obtain Lacosamide impurity-C.

The suitable base employed in this reaction can be selected from organic base, where in the organic base is selected from diisopropylethylamine, triethylamine, isopropylamine, diisopropylamine, N-methyl morpholine, N-methyl piperidine, N-methyl piperazine or N-methyl pyridine. Preferably triethylamine.
The reaction temperature may range from 35-60 °C and preferably at a temperature in the range from 40-45 °C. The duration of the reaction may range from 8-16 hours, preferably for a period of 12 hours.

Compound of formula-IV is reacted with aqueous sodium hydroxide solution followed by heating the resulting reaction mixture to a suitable temperature. Neutralize the reaction mixture with concentrated hydrochloric acid and extracted with methylene chloride. The obtained organic layer is distilled and resulting residue is purified by column chromatography to obtain Lacosamide impurity-K.
The reaction temperature may range from 50-90 °C and preferably at a temperature in the range from 75-80 °C. The duration of the reaction may range from 1-5 hours, preferably for a period of 1 hour.

Scheme-III illustrates the process for the preparation of Lacosamide impurity-H.

In step-1, compound of formula-V reacted with di tert-butyl dicarbonate in presence of a suitable base and extracted with a suitable organic solvent followed by evaporation to give compound of formula-VI as a residue.
The suitable base employed in this reaction can be selected from organic base or inorganic base where in the organic base is selected from diisopropylethylamine, triethylamine, isopropylamine, diisopropylamine, N-methyl morpholine, N-methyl piperidine, N-methyl piperazine or N-methyl pyridine and inorganic base is selected from sodium hydroxide, sodium carbonate, potassium hydroxide or potassium carbonate. Preferably sodium hydroxide.
The suitable organic solvent may be selected from ester solvents or chloro solvents. Preferably ethyl acetate.

In step-2, the residue obtained in step-1 is dissolved in water followed by reacting with methyl iodide in presence of aqueous sodium hydroxide to obtain compound of formula-VII.
In step-3, compound of formula-VII condensed with compound of formula-VIII in presence of a suitable condensation agent and a suitable base followed by deprotecting with concentrated hydrochloric acid to obtain compound of formula-IX.
The suitable condensation agent may be selected from N,N'-Dicyclohexyl carbodiimide (DCC) in presence of hydroxybenzotriazole (HOBT), 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl) in presence of hydroxybenzotriazole (HOBT), N,N'-Dicyclohexyl carbodiimide (DCC) in presence of 4-Dimethylaminopyridine (DMAP) and preferably EDC.HCl in HOBt.
In step-4, compound of formula-IX reacted with acetic anhydride in a suitable solvent to obtain
Lacosamide impurity-H.
The suitable solvent used in this reaction is selected from chloro solvent, alcohol solvent,
hydrocarbon solvents, nitrile solvents, ether solvents, ester solvents or polar aprotic solvents and
preferably using dichloromethane.
Scheme-IV illustrates the process for the preparation of Lacosamide impurity-I


Scheme-IV
Compound of formula-X is reacted with a suitable hydrochloride source followed by reacting with isocyanatomethylbenzene in presence of a suitable base and quenched the resulted reaction mixture with water. Extracted the reaction mixture with a suitable solvent and filtered to obtain Lacosamide impurity-I.
The suitable hydrochloride source is selected from methanolic hydrochloric acid, Isopropanolic hydrochloric acid or hydrogen chloride gas. Preferably methanolic hydrochloride.
The suitable base employed in this reaction can be selected from organic base or inorganic base where in the organic base is selected from diisopropylethylamine, triethylamine, isopropylamine, diisopropylamine, N-methyl morpholine, N-methyl piperidine, N-methyl piperazine or N-methyl pyridine or inorganic base is selected from sodium hydroxide, sodium carbonate, potassium hydroxide or potassium carbonate. Preferably triethylamine.
The suitable solvent used in this reaction is selected from chloro solvent, alcohol solvent, hydrocarbon solvents, nitrile solvents, ether solvents, ester solvents or polar aprotic solvents and preferably using dichloromethane.
The reaction temperature may range from 20-40 °C and preferably at a temperature in the range from 25-30 °C. The duration of the reaction may range from 2 to 4 hours, preferably for a period of 2 hours.
EXPERIMENTAL PORTION
The details of the invention are given in the examples provided below, which are given to illustrate the invention only and therefore should not be construed to limit the scope of the invention.
Example-1: Process for the preparation of Lacosamide impurity-C
Stage-1: Synthesis of N-benzyl-3-methoxy-2-(methylamino)propanamide
40% aqueous methylamine solution (100 mL) was added to a mixture of N-benzyl-3-methoxy-2-{[(4-methyl phenyl)sulfonyl]methyl}propanamide (20 grams) and dimethylformamide (30 mL) at 25-30 °C. The resulting reaction mixture was heated to 40-45 °C for 12 hours, after consumption of the starting material, reaction mixture was cooled to 0-5 °C. Water (200 mL) and

dichloromethane (200 mL) were added to the reaction mixture and stirred for 15 minutes at 25-30 °C. Both the aqueous and organic layers were separated. Aqueous layer was extracted with dichloromethane. Combined the organic layers and volatiles were removed under reduced pressure to get the title compound. Yield: 5 grams.
Stage-2: Synthesis of (2E)-N-benzyl-3-methoxy-2-(N-methylacetamido)-propanamide
Compound obtained in stage-1 (5 grams) was suspended in tetrahydrofuran (100 mL) and triethylamine (3.68 grams) was charged to the resulting reaction mixture at 25-30 °C and stirred for 10 minutes at the same temperature. Acetic anhydride (3.4 grams) was slowly added to the reaction mixture and stirred for one hour at 25-30 °C. Volatiles were evaporated under reduced pressure and dichloromethane (70 mL) was added to the resulting reaction mixture. Neutralize the reaction mixture with 10% aqueous sodium bicarbonate solution and both the organic and aqueous layers were separated. Combine the organic layers and volatiles were evaporated under reduced pressure. The obtained residue was purified with column chromatography [Ethyl acetate: hexane] to get the title compound. Yield: 2.5 grams.
Example-2: Process for the preparation of Lacosamide impurity-K
N-benzyl-3-methoxy-2-(methylamino)propanamide (20 grams) was dissolved in aqueous sodium hydroxide solution (60 mL) at 25-30 °C and stirred for 10 minutes at the same temperature. Heated the resulting reaction mixture to 75-80 °C and stirred for 1 hour at the same temperature. After consumption of the starting material, temperature of the reaction mixture was cooled to 25-30 °C and neutralize with concentrated hydrochloric acid (2 mL) followed by extracting with dichloromethane (200 mL). Both the organic and aqueous layers were separated, washed the organic layer with water. Volatiles were evaporated from the obtained organic layer under reduced pressure. The resulting residue was dissolved in ethyl acetate and stirred for 1 hour at 25-30 °C. Filtered the precipitated solid and volatiles were removed from the obtained filtrate under reduced pressure. The obtained residue was purified by column chromatography [ethyl acetate: hexane] to get the title compound. Yield: 1 gram.

Example-3: Process for the preparation of Lacosamide impurity-H
Stage-1: Synthesis of 2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoic acid:
Aqueous sodium hydroxide solution (75 mL) was slowly added to a mixture of D-serine (20 grams) and water (40 mL) with in a period of 45 minutes at 25-30°C. Di tert-butyl dicarbonate (65.4 grams) was slowly added to the resulting reaction mixture with in 1 hour, after completion of addition, stirred for 6 hours at 25-30 °C. Filtered the unwanted solid and washed with water. Acidify the obtained filtrate with aqueous hydrochloric acid solution at 0-10 °C. Temperature of the reaction mixture raised to 25-30 °C and extracted with ethyl acetate. Combine the organic layers and volatiles were removed from the organic layer under reduced pressure to get the title compound. Yield: 30 grams.
Stage-2: Synthesis of 2-[(tert-butoxycarbonyl)amino]-3-methoxypropanoic acid
Compound obtained in stage-1 (10 grams) was dissolved in water at 25-30 °C and stirred for 10 minutes at the same temperature. Methyl iodide (13.8 grams) and aqueous sodium hydroxide solution (12 mL) were added to the resulting reaction mixture at 25-30 °C with in a period of 45 minutes and stirred for 6 hours at the same temperature. Acidify the reaction mixture with aqueous citric acid solution at 0-10 °C. The reaction mixture was extracted with dichloromethane and both the organic and aqueous layers were separated. Combined the organic layers and volatiles were removed under reduced pressure to get the title compound. Yield: 7 grams.
Stage-3: Synthesis of 4-amino-N-benzyl-5-methoxy-2-(methoxymethyl)-3-oxopentanamide
Compound obtained in stage-2 (7 grams) was suspended in a mixture of dichloromethane (70 mL) and 2-amino-N-benzyl-3-methoxypropanamide (5.98 grams) at 25-30 °C. Hydroxybenzotriazole (4.8 grams), 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (6.9 grams) and N-methyl morphline (6.4 grams) were added to the reaction mixture at 0-10 °C. Temperature of the reaction mixture was raised to 25-30 °C and stirred for 12 hours at the same temperature. Water (70 mL) was added to the reaction mixture and stirred for 15 minutes. Both the organic and aqueous layers were separated and aqueous layer was extracted with dichloromethane. Combine the organic layers and volatiles were removed from the organic layer under reduced pressure. The obtained residue was dissolved in dichloromethane and stirred for 10 minutes at 25-30 °C. Hydrochloric acid (30 mL) was added to the resulting reaction mixture at 10-20 °C and stirred for 1 hour at the same temperature. Both the organic and aqueous layers were separated and aqueous layer was neutralized with aqueous sodium carbonate solution (55 mL) at 25-30 °C. The reaction

mixture was extracted with dichloromethane and volatiles were removed from the organic layer under reduced pressure to get the title compound. Yield: 6.5 grams.
Stage-4: Synthesis of Lacosamide impurity-H
Compound obtained in above stage-3 (6.5 grams) was suspended in dichloromethane (65 mL) and stirred for 10 minutes for clear dissolution. Acetic anhydride (2.5 grams) was slowly added to the reaction mixture at 0-10 °C. Temperature of the reaction mixture raised to 25-30 °C and stirred for 30 minutes at the same temperature. Quenched the reaction mixture with water (65 mL) and stirred for 15 minutes. Both the organic and aqueous layers were separated and volatiles were removed from the organic layer under educed pressure. The obtained residue was dissolved in ethyl acetate (26 mL) and stirred for 30 minutes at 25-30 °C. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound. Yield: 4.3 grams.
Example-4: Process for the preparation of Lacosamide impurity-I
Methanolic hydrochloric acid (20 mL) was added to 2-amino-N-benzyl-3-methoxypropanamide (5 grams) and volatiles were removed under reduced pressure. The resulting residue was suspended in dichloromethane (60 mL). Triethylamine (10 mL) and benzyl isocyanate (3.1 mL) were added to the reaction mixture at 25-30 °C and stirred for 2 hours at the same temperature. After consumption of the starting material, ethyl acetate (50 mL) and water (50 mL) were added to the reaction mixture, stirring the reaction mixture for 30 minutes. Filtered the precipitated solid, washed with n-hexane and dried to get the title compound. Yield: 4 grams.

We claim:
1. A process for the preparation of Lacosamide impurity-C

which comprises;
a) reaction of compound of formula-II

with 40 % aqueous methylamine solution in dimethylformamide to give compound of formula-III;

b) acylation of compound of formula-III with acetic anhydride in presence of
triethylamine to obtain Lacosamide impurity-C.
2. A process for the preparation of Lacosamide impurity-K

which comprises:

a) treatment of compound of formula-IV

with aqueous sodium hydroxide solution to obtain Lacosamide impurity-K. 3. A process for the preparation of Lacosamide impurity-H

which comprises;
a) reaction of compound of formula-V

with Di-tert-butyl dicarbonate in presence of sodium hydroxide to give compound of formula-VI;

b) methylation of compound of formula-VI with methyl iodide in presence of sodium
hydroxide to give compound of formula-VII;

c) condensation of compound of formula-VII with compound of formula-VIII

in presence of hydroxy benzotriazole and 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride followed by deprotecting with hydrochloric acid to give compound of formula-IX;

d) N-acylation of compound of formula-IX with acetic anhydride to obtain
Lacosamide impurity-H.

4. A process for the preparation of Lacosamide impurity-I

which comprises;
a) treatment of compound of formula-X

with methanolic hydrochloric acid to give compound of formula-XI;

b) condensation of compound of formula-XI with isocyanatomethylbenzene in
presence of triethylamine to obtain Lacosamide impurity-I.