FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10, rule 13)
1. Title of the invention
"Process for preparation of Lacosamide"
2. Applicant(s)
Name Nationality Address
USV Limited Indian company incorporated B.S.D. Marg Station Road, Govandi, Mumbai-400 088,
under Companies Act, 1956 Maharashtra India
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 an improved process for preparation of (R)-2-acetamido-N-benzyl-3-methoxypropionamide, also known as Lacosamide. The present invention also relates to a process for preparation of (R)-N-benzyl-2-amino-3-hydroxypropionamide or salts thereof, an intermediate used in the synthesis of Lacosamide.
Background of the invention:
Lacosamide (SPM 927, SPM 929, ADD 234037, also referred to as Harkoseride or Erlosamide), is chemically the (R)-enantiomer, (R)-2-acetamido-N-benzyI-3-methoxypropionamide of the following formula (I).

Lacosamide is marketed under the trade name Vimpat® by UCB Inc. Lacosamide is indicated for adjunctive treatment of partial-onset seizures. Lacosamide is available as tablets (50mg, 100mg, 150mg and 200mg), oral solution (10mg/ml and 15mg/ml) and as a solution for intravenous administration (200mg/20ml) for cases where oral dosing is not possible. Lacosamide is a functionalized amino acid that has dual mechanism of action. In vitro, electrophysiological studies have shown that lacosamide selectively enhances slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing. Lacosamide binds to collapsin response mediator protein-2, a phosphoprotein which is mainly expressed in the nervous system and is involved in neuronal differentiation and control of axonal outgrowth.
W09733861 discloses three methods for the preparation of Lacosamide. The first method involves acylation of D-serine (II) to give the corresponding acetyl derivative followed by treatment of acetyl derivative with benzylamine under mixed anhydride coupling reaction conditions to provide the corresponding amide derivative and lastly

methylation of the amide derivative by employing methyl iodide in presence of silver oxide to obtain Lacosamide.
This reaction is represented in Scheme I as below;

Scheme I
Second method involves esterification of D-serine (II) with an alcohol to provide the corresponding ester, which is reacted with excess of benzylamine at reflux temperature to form the corresponding amide.
This reaction is represented in Scheme II as below:

Acylation of free amino group of the amide derivative with acylating agents such as acetic anhydride, acetic acid or lower alkyl ester of acetic acid provides the acetyl

derivative. Methylation of the acetyl derivative using methyl iodide in presence of silver oxide provides the product of formula (I).
Third process gives the synthesis of Lacosamide as presented in Scheme III which involves the O-methylation of N-protected-D-serine prior to benzylamine formation followed by N-deprotection and N-acylation.

Scheme III
The first two methods do not involve the protection of active groups in the intermediate compounds such as amino, hydroxy or carboxylic acid groups. The third method involves the protection of the amino group followed by introduction, of benzylamine group and removal of the 'Cbz' group (protecting group) and finally acetylation to obtain lacosamide.
The above mentioned two methods involve the acylation of amide derivative by using acetic anhydride which leads to formation of N,0 diacetyl by-product. Also the methods of preparation involve the use of methyl iodide in presence of silver oxide as

O-methylation agent. This process is expensive and leads to partial racemization of the compound undergoing the O-methylation, which reduces the yield of the process and increases the cost. Moreover the above described methods take long reaction time, nearly four days for the completion of reaction which is a main drawback in terms of industrial productivity.
WO2006037574 describes the method for the preparation of lacosamide wherein the methylation step is carried out using dimethylsulphate in the presence of n-butyl lithium or aqueous sodium hydroxide. Optionally phase transfer catalyst is used . This document mentions that this process does not result in methyl ester formation or significant racemisation of the product. It further mentions that the inventive O-methylation can be achieved by treating D-serine or N-protected-D-serine with a methylating agent in presence of an organometal compound, in particular organolithium compound. Use of n-butyl lithium at industrial scale is undesired since n-butane, a highly flammable gas, is obtained as a by-product of the reaction.
The reaction is represented in Scheme IV as below:



Scheme IV
US20090143472 discloses the preparation of Lacosamide by making use of a bulkier group, trityl group other than "Boc" and "Cbz". The intermediate compounds comprise bulky protecting groups that are capable of minimizing nucleophilic attack at chiral carbon atom, which is otherwise responsible for racemization. But methylation of trityl derivative at the initial stage to provide trityl methoxy derivative decreases the reactivity of trityl derivative and increases reaction time thereby affecting the overall reaction time.
The reaction is represented in Scheme V as below:

(I) Scheme V
WO2009146325 discloses the polymorphic forms of Lacosamide and process of
preparation thereof.

WO2010107993 discloses process for preparation of (R)-N-benzyl-2-(benzyIoxy carbonyIamino)-3-methoxypropionamide, an intermediate of lacosamide by combining the (R)-N-benzyl-2-(benzyloxycarbonylarnino)-3-hydroxy propionamide with dimethylsulphate, followed by mixing with alkali or alkaline earth metal hydroxide at a temperature of about 25°C to about -15°C. (R)-N-benzyl-2-(benzyloxycarbonylamino)-3-methoxypropionamide is further converted to lacosamide. This process avoids the use of methyl iodide and silver oxide thereby avoiding the formation of N-methylated impurity.
WO2011092672 discloses a process for preparation of lacosamide comprising the steps of treating D- serine with a protecting reagent, wherein number of moles of the protecting reagent is less than the number of moles of D-serine, to obtain N-protected-D-serine; O-methylating the obtained N-protected-D-serine to produce O-methyl-N-protected-D-serine; benzylaminating O-methyl-N-protected-D-serine to produce N-benzyl-0-metnyl-N2-protected-D-serinamide; deprotecting N-benzyl-O-methyl-N2-protected-D-serinamide to produce N-benzyl-O-methyl-D-serinamide; and acetylating N-benzyl-0-methyl-D-serinamide in aqueous medium to produce Lacosamide. It further discloses a process for reducing the content of "Impurity-A" [(2R)-2-(acetylamino)-3-(benzylamino)-3-oxopropylacetate] in lacosamide during the preparation of lacosamide that comprises the step of treating D-serine with a protecting reagent wherein the number of moles of the protecting reagent is less than the number of moles of D-serine. It further discloses a process for reducing the content of "Impurity-B" [(2R)-2-propanoylamino-N-benzyl-3-methoxypropionamide] in Lacosamide that comprises the step of acetylating N-benzyl-O-methyl-D-serinamide in aqueous medium. The process of the present invention uses slightly higher amount of protecting reagent with respect to D-serine. This is necessary to ensure the completion of reaction. However, it is found that the process of the present invention produces Lacosamide substantially free of Impurity A and Impurity B,
WO2011144983 provides a process for the preparation of Lacosamide comprising O-methylation of Acetyl-D-serinamide in the presence of methylating agent and a base

with proviso that the O-methylation is not carried out in the presence of silver oxide. The examples indicate that dichloromethane is the solvent used for benzylamination, acetylation and methylation. The disadvantage of using dichloromethane for these reactions are poor selectivity, low yield and longer reaction time.
WO2011099033 discloses processes for preparing and purifying Lacosamide. WO'033 discloses O-methylation of (R)-2-acetamido-N-benzyl-3-hydroxypropanamide with dimethyl sulfate in presence of aqueous sodium hydroxide solution, tetrabutylammonium bromide and toluene to provide Lacosamide. It has been found that O-methylation of (R)-2-acetamido-N-benzyl-3-hydroxy propanamide in toluene leads to formation of impurity due to its less solubility in toluene. Besides, the reaction in toluene takes longer time for completion and results in a sticky product. Use of THF-water or dichloromethane-water as solvent medium as used in the process of the present invention for methylation ensures faster reaction and easy work-up.
There exists a need for simple, eco-friendly, robust and commercially viable process for the preparation of lacosamide. The present process provides improved efficiency per reaction volume in terms of good yields and purity of the product.
Object of the invention:
An object of the present invention is to provide a simple, eco-friendly and commercially viable process for the preparation of Lacosamide.
Another object of the present invention is to provide an industrially viable process for the preparation of (R)-N-benzyl-2-amino-3-hydroxypropionamide or salts thereof.
Summary of the Invention:
The present invention discloses a simple, eco-friendly and commercially viable process for the preparation of Lacosamide.
According to one aspect of the present invention, process for preparation of Lacosamide comprising the steps of,
a) treating (R)-N-benzyI-2-amino-3-hydroxypropionamide or salt thereof with an

acetylating agent in presence of metal oxide to get (R)-N-benzyl-2-acetamido hydracrylamide; and b) converting (R)-N-benzyl-2-acetamido hydracrylamide to Lacosamide.
Preferably, metal oxide is selected from magnesium oxide, zinc oxide, aluminum oxide, copper oxide or cobalt oxide; said acetylating agent is selected from acetyl chloride, acetic anhydride or acetic acid. Preferably, treatment with acetyl chloride is carried out in presence of tetrahydrofuran-water or 1,4-dioxane-water at a temperature of 0 to 10°C.
Another aspect of the present invention provides a process for preparation of (R)-N-benzyl-2-amino-3-hydroxypropionamide comprising the steps of,
a) benzylaminating N-protected-D-serine in presence of a carbonyl group activator to obtain 2(R)-(N-protected)amino-N-benzyl-3-hydroxy propionamide;
b) optionally, isolating 2(R)-(N-protected)-amino-N-benzyl-3-hydroxy propionamide; and
c) deprotecting 2(R)-(N-protected)-amino-N-benzyl-3-hydroxy propionamide to obtain (R)-N-benzyl-2-amino-3-hydroxy propionamide or salt thereof.
Preferably, carbonyl group activator is isobutyl chloroformate or pivaloyl chloride; benzylamination is carried out in the presence of N-methyl morpholine and tetrahydrofuran at a temperature of-50 to 10°C; and deprotection is carried out using a mineral acid. Preferably,N-protected-D-serine is N-Boc-D-serine prepared by a process comprising treating D-serine with di-tert-butyl dicarbonate.
Another aspect of present invention provides conversion of (R)-N-benzyl-2-amino-3-hydroxypropionamide or salt thereof to Lacosamide by O-methylation of (R)-N-benzyl-2-acetamido hydracrylamide.
Preferably, O-methylation is carried out using dimethyl sulphate in the presence of base selected from sodium hydroxide or potassium hydroxide and phase transfer catalyst selected from tetrapropyl ammonium hydroxide, tetrabutyl ammonium halide such as tetrabutyl ammonium bromide, tetrabutyl ammonium chloride or tetrabutyl

ammonium iodide.
Another aspect of the present invention provides a process wherein acetylation of (R)-N-benzyl-2-amino-3-hydroxypropionamide and O-methyiation of acetylated product is carried out in one-pot, without isolation of the acetylated product.
Another aspect of the present invention provides a process wherein conversion of N-Boc-D-serine to (R)-N-benzyl-2-acetamido hydracrylamide is carried out in one-pot.
Brief Description of Drawing:
Fig. 1: X-ray Powder Diffraction of Lacosamide Form I.
Detailed description of the invention:
The present invention relates to a simple, eco-friendly and commercially viable process for the preparation of Lacosamide of formula (I) by avoiding the use of hazardous reagents and expensive catalyst.

According to one embodiment of the present invention, there is provided a process for preparation of Lacosamide of formula (I) comprising the steps of,
a) treating (R)-N-benzyl-2-amino-3-hydroxypropionamide (V) or salt thereof with an acetylating agent in presence of metal oxide to get (R)-N-benzyl-2-acetamido hydracrylamide (VI); and
b) converting (R)-N-benzyl-2-acetamido hydracrylamide (VI) to Lacosamide.
Metal oxide is selected from magnesium oxide, zinc oxide, aluminum oxide, copper oxide or cobalt oxide, preferably magnesium oxide. Acetylating agent is selected from acetyl chloride, acetic anhydride, acetic acid or the like. Acetylation is carried out in a solvent selected from tetrahydrofuran, 1,4-dioxane, ethyl acetate or mixture thereof.


According to a preferred embodiment of the present invention, (R)-N-benzyl-2-amino-3-hydroxypropionamide (V) or salt thereof is acetylated using acetyl chloride in presence of magnesium oxide and solvent selected from tetrahydrofuran or 1,4-dioxane to get (R)-N-benzyl-2-acetamido hydracrylamide (VI). Optionally a base selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide or mixture thereof can be used.
Preferably, magnesium oxide and tetrahydrofuran are added to an aqueous suspension of (R)-N-benzyl-2-amino-3-hydroxypropionamide (V) or salt thereof to obtain a reaction mixture. The obtained reaction mixture is cooled to a temperature of 0 to 10°C followed by dropwise addition of acetyl chloride. The reaction mixture is gradually warmed to room temperature. The solvent is distilled off under reduced pressure to obtain a solid. The obtained solid is treated with an ether selected from methyl tert butyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran or 1,4-dioxane and the mixture is filtered to obtain get (R)-N-benzyl-2-acetamido hydracrylamide (VI).
Acetic anhydride, being a controlled substance is preferably avoided in the present process. Besides, use of acetic anhydride and pyridine as reported in the prior art increases the reaction time or the reaction does not proceed to completion. The present invention involves the use of aqueous medium during acetylation reaction thereby avoiding the formation of O-acylated derivatives of compound (V) or compound (VI) thus avoiding the additional step of removing the O-acetylated derivatives. The present invention carries the acetylation reaction in presence of metal oxide such as magnesium oxide. Metal oxide such as magnesium oxide or zinc oxide are preferred in chemical reactions because of its high chemoselectivity, environmental compatibility, simplicity

of operation and low cost.
Another embodiment of the present invention provides conversion of (R)-N-benzyl-2-acetamido hydracrylamide (VI) to Lacosamide by a process comprising methylating (R)-N-benzyl-2-acetamido hydracrylamide (VI) using dimethyl sulphate in the presence of alkali or alkaline earth metal hydroxide and phase transfer catalyst.

O-methylation reaction is carried out in a solvent selected from tetrahydrofuran (THF), ethyl acetate, methyl acetate, acetonitrile, acetone, dichloromethane or water, preferably tetrahydrofuran-water or dichloromethane-water.
The phase transfer catalyst used for O-methylation is selected from ammonium, phosphonium or pyridinium salts. Preferably the phase transfer catalyst is selected from benzyltriethylammonium halide, butyltriethyl ammonium halide, methyl triphenyl phosphonium halide, tetrapropyl ammonium hydroxide and tetrabutyl ammonium halides, preferably tetrabutyl ammonium halide such as tetrabutyl ammonium bromide, tetrabutyl ammonium chloride or tetrabutyl ammonium iodide, more preferably tetrabutyl ammonium bromide.
In a preferred embodiment, to a mixture of compound (VI), phase transfer catalyst and alkali metal hydroxide, is added a mixture of water and tetrahydrafuran. Dimethyl sulphate is then added to this mixture at a temperature of 0 to 10°C. The reaction is usually allowed to proceed for 0.5-8 hours, preferably for 1-6 hours. The O-methylated compound is then isolated from the mixture. The crude Lacosamide thus obtained has purity greater than 98%. Lacosamide thus obtained is optionally purified.
Other methylating agent which can be used for O-methylation is selected from trimethylsilyl diazomethane or trimethyl phosphate.

Optionally, Lacosamide obtained is subjected to treatment using solvent selected from ester, ether, nitrile or hydrocarbon. Ester is selected from C1-6 ester such as methyl acetate, ethyl acetate, butyl acetate or mixture thereof. Ether is selected from diethyl ether, methyl-t-butylether, tetrahydrofuran or 1,4-dioxane, preferably tetrahydrofuran. Nitrile is selected from acetonitrile, propionitrile or the like. Hydrocarbon is selected from pentane, hexane, toluene or xylene.
Prior art reports O-methylation reaction prior to benzylamination process. It has been found that if O-methylation is carried out at the initial stage, then the reaction slows down which affects the overall reaction time. In order to avoid the difficulties and smooth functioning of the reaction, the present invention involves benzylamination step prior to O-methylation.
The amount of methylating agent for O-methylation is 1-5 molar equivalent with respect to compound of formula (VI), the aqueous alkali is 1-7 molar equivalent with respect to compound of formula (VI), organic solvent is 5-25 volumes with respect to compound of formula (VI) and the amount of phase transfer catalyst is between 0.01 to 0.1 molar equivalent with respect to compound of formula (VI).
Methyl iodide is generally used as reagent for O-methylation. Use of methyl iodide is preferably avoided as iodides are generally expensive relative to more common chlorides and bromides. The iodide leaving group in methyl iodide may cause side reactions as it is a powerful nucleophile and these side reactions can result in the formation of N-alkylated impurity in the final product. In order to avoid the formation of N-alkylated impurity, use of dimethyl sulphate is preferred in the present invention, as it is cheap compared to methyl iodide. Its high reactivity increases the rate of reaction and the yield of the product.
In an alternate embodiment, O-methylation process of compound of formula (VI) is performed by using methyl iodide as methylating agent in presence of base and optionally in the presence of phase transfer catalyst. The base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or cesium

carbonate. The solvent is selected from polar aprotic solvent such as dimethylformamide, acetonitrile or tetrahydrofuran.
According to another embodiment of the present invention, there is provided a process for preparation of (R)-N-benzyl-2-amino-3-hydroxypropionamide (V) or salt thereof comprising the steps of,
a) benzylaminating N-protected-D-serine in presence of a carbonyl group activator to obtain 2(R)-(N-protected) amino-N-benzyl-3-hydroxypropionamide;
b) optionally, isolating 2(R)-(N-protected)-amino-N-benzyl-3-hydroxy propionamide; and
c) deprotecting 2(R)-(N-protected)-amino-N-benzyl-3-hydroxypropionamide to obtain (R)-N-benzyl-2-amino-3-hydroxypropionamide (V) or salt thereof.
Preferably, N-protected-D-serine is N-Boc-D-serine.
Preferably, 2(R)-(N-protected) amino-N-benzyl-3-hydroxy propionamide is 2(R)-N-
Boc-amino-N-benzyl-3-hydroxypropionamide.

Carbonyl group activator is selected from alkyl or aryl chloroformate such as isobutyl chloroformate (IBCF), pivaloyl chloride, methyl chloroformate, phenyl chloroformate, nitrophenyl chloroformate, preferably isobutyl chloroformate or pivaloyl chloride. Benzylamination reaction is carried out in presence of base selected from N-methyl morpholine (NMM), diethyl amine, triethylamine or N,N-diisopropylethyl amine, preferably N-methyl morpholine at a temperature in the range of -50°C to 10°C. Solvent for benzylamination is selected from ether, ester, aromatic hydrocarbon, water or mixture thereof. Ether is selected from diethyl ether, methyl-t-butyl ether, diisopropyl ether, tetrahydrofuran or 1,4-dioxane. Ester is selected from C1-6 ester such as ethyl acetate, methyl acetate, butyl acetate, isobutyl acetate. Aromatic hydrocarbon is selected from toluene or xylene.

In a preferred embodiment, N-Boc-D-serine and N-methyl morpholine (NMM) are taken in tetrahydrofuran to obtain a reaction mixture. The reaction mixture is cooled to a temperature of -50°C to 5°C, preferably -40°C to 0°C under nitrogen followed by dropwise addition of carbonyl activator such as isobutyl chloroformate or pivaloyl chloride. This reaction mixture is stirred for 20 to 40 min, preferably for 30 minutes followed by gradual addition of benzylamine at the same temperature. The reaction mixture is warmed to room temperature, preferably 25 to 35°C and stirred for 0.5 to 4 hours, preferably for 0.5-2 hours, more preferably for 1 hour. This reaction mixture is filtered to remove the N-methyl morpholine (NMM) hydrochloride and the filtrate is concentrated under reduced pressure to obtain a residue. This residue is treated with an ester and the resultant mixture is washed with an aqueous solution of citric acid. The organic layer is separated, dried and concentrated to obtain an oily residue. This oily residue is further purified using an ether to obtain 2(R)-N-Boc-amino-N-benzyl-3-hydroxy propionamide as a solid.
The carbonyl moiety present in compound (III) forms an amide group with -NH2 moiety of benzylamine. The carbonyl group present in compound (III) needs activation before the benzylamination reaction. Formation of an amide from a carboxylic acid and an amine often results in overall loss of free energy however there is a high activation energy to be overcome. This is achieved either by catalysis or by formation of carboxylic acid derivatives. The nature of the leaving group governs the value of the activation energy. The present process uses isobutyl chloroformate or pivaloyl chloride. Pivaloyl chloride are the most preferred carboxylic acid activating agent. The advantage of using the pivaloyl chloride is that the reaction can be carried out at the temperature of about -10 to 5°C, preferably -5°C to 0°C making the process industrially feasible. It has been found that the reaction using isobutyl chloroformate as carbonyl activator has to carried out at -40°C to -10°C which is not industrially feasible.
In accordance with a preferred embodiment, deprotection of 2(R)-N-Boc-amino-N-benzyl-3-hydroxypropionamide is carried out in presence of mineral acid selected from hydrochloric acid, sulphuric acid, nitric acid or phosphoric acid in a suitable solvent selected from alcohol, ester, water or mixture thereof, preferably alcohol such as C1-4

alcohol selected from methanol, ethanol or isopropyl alcohol to obtain (R)-N-benzyl-2-amino-3-hydroxypropionamide or salt thereof (V).

Preferably, 2(R)-N-Boc-amino-N-benzyl-3-hydroxypropionamide (IV) in isopropyl alcohol is treated with conc, hydrochloric acid to obtain a reaction mixture. This reaction mixture is stirred for 0.5 to 1.5 hours, preferably for 1 hour at room temperature. The solvent is removed from the reaction mixture under reduced pressure to obtain a solid. The solid thus obtained is further treated with ether selected from methyl tert butyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, preferably methyl tert butyl ether.
The starting materials, N-Boc-D-serine (III) is a commercial product. N-Boc-D-serine can be prepared by any method known in the art.
Preferably, N-Boc-D-serine (III) is prepared by a process comprising the steps of, protecting D-serine using di-tert-butyl dicarbonate (Boc anhydride) in presence of a base selected from sodium hydroxide, potassium hydroxide, ammonia, sodium hydride, potassium tertiary butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, cesium hydroxide or mixture thereof and a suitable solvent selected from 1,4-dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofiiran or mixture thereof to obtain a reaction mixture. This reaction mixture is stirred at room temperature for 3 to 6 hours, preferably for 4 hours followed by addition of potassium bisulphate to achieve the pH of 2-3. The reaction mixture is extracted using organic solvent selected from ethyl acetate, methyl acetate, butyl acetate or isobutyl acetate. The organic layer is evaporated to obtain N-Boc -D-serine (HI) as an oil.


(II) (III)
In a preferred embodiment of the present invention, there is provided a process for the preparation of Lacosamide comprising the steps of,
a) benzylaminating N-protected D-serine in presence of isobutyl chloroformate or pivaloyl chloride to obtain 2(R)-(N-protected)-amino-N-benzyl-3-hydroxypropionamide;
b) deprotecting 2(R)-(N-protected)-amino-N-benzyl-3-hydroxypropionamide in presence of mineral acid to obtain (R)-N-benzyl-2-amino-3-hydroxy propionamide or salt thereof;
c) acetylating (R)-N-benzyl-2-amino-3-hydroxypropionamide or salt thereof in presence of metal oxide to get (R)-N-benzyl-2-acetamido hydracrylamide;
d) methylating (R)-N-benzyl-2-acetamido hydracrylamide to get Lacosamide; and
e) optionally purifying Lacosmide.
Another embodiment of the present invention provides a one-pot process for the preparation of Lacosamide wherein (R)-N-benzyl-2-acetamido hydracrylamide (VI) obtained after the acetylation reaction of (R)-N-benzyl-2-amino-3-hydroxy propionamide or salt thereof is not isolated and is subjected to insitu O-methylation to Lacosamide. This in situ process saves considerable time and hence is considered to be an industrially viable process.
Another embodiment of the present invention provides an industrially viable process for the preparation of (R)-N-benzyl-2-amino-3-hydroxypropionamide (V) or salt thereof, without purification of the intermediates, comprising the steps of,
a) treating D-serine with di-tert-butyl dicarbonate in ether solvent to get an oily product which is used as such for the further reaction;
b) treating the oily product from step a) with a carbonyl group activator and benzylamine to obtain an oily product, which is used as such for the further

reaction, without purification; c) treating the oily product from step b) with mineral acid to obtain (R)-N-benzyl-2-amino-3-hydroxypropionamide(V) or salt thereof in high yield and purity.
The intermediate compounds are not purified and are used as such for the further reaction.
Lacosamide obtained according to the present invention has high chiral purity in which no detectable amount of corresponding S-enantiomer is present. Lacosamide prepared by following the process of the present invention is at least about 99% pure, preferably at least about 99.8% pure and more preferably greater than about 99.8% pure.
In another embodiment, Lacosamide obtained is purified by a process comprising the steps of,
a) dissolving Lacosamide in suitable solvent;
b) isolating pure Lacosamide.
The dissolution is carried out at a temperature of 70-75°C or at the reflux temperature of the solvent selected for dissolution. The solution is optionally filtered to remove insoluble particles and cooled to a temperature of 0-5°C. Lacosamide obtained according to present invention is substantially free of other impurities and has chemical purity of more than about 99.8% with all known impurities below 0.15% and unknown impurities below 0.1%.
Another embodiment of the present invention provides process for preparation of pure Lacosamide comprising the steps of,
a) dissolving Lacosamide in suitable solvent to get first solution;
b) optionally filtering the first solution of step a);
c) adding antisolvent to the solution of step a) or step b);
d) isolating pure Lacosamide.
The dissolution is carried out at a temperature of 70-75°C or at the reflux temperature

of the solvent selected for dissolution. The solution is optionally filtered to remove insoluble particles. An antisolvent is added to the solution of Lacosamide either before or after cooling. Lacosamide thus obtained according to the present invention is substantially free of other impurities and has chemical purity of more than 99.8% with all known impurities below 0.15% and unknown impurities below 0.1%.
Suitable solvent is selected from ester, ether, nitrile, water or mixture thereof Ester is selected from C1-6 ester such as methyl acetate, ethyl acetate or butyl acetate. Ether is selected from diethyl ether, methyl-t-butyl ether, tetrahydrofuran or 1,4-dioxane. Nitrile is selected from C1-4 nitrile such as acetonitrile or propionitrile. Antisolvent is selected from hydrocarbon, ether, water or mixture thereof. Hydrocarbon is selected from pentane, hexane or heptane. Ether is selected from tetrahydrofuran or 1,4-dioxane.
In a preferred embodiment, Lacosamide obtained by the process of the present invention is found to be polymorphic Form I. Lacosamide crystalline Form I is characterized by X-ray diffraction pattern as shown in Fig. 1 and is further characterized by peaks at 20 value of about 6.47, 8.28, 10.38, 12.97, 15.58, 16.56, 17.63, 19.50, 21.0, 21.41, 24.26, 24.94, 25.32, 25.65, 26.09, 27.16, 28.40, 30.67, 31.45, 32.27, 32.76, 33.51, 34.07, 36.51,40.26,40.73,41.10,45.07 and 46.93 ±0.2 degrees.
Lacosamide obtained according to present invention has particle size distribution such that 90% particles have particle size less than about 500 microns which may be micronized using conventional micronization techniques to get reduced particle size, suitable for pharmaceutical formulation. Preferably, Lacosamide obtained according to present invention has particle size distribution such that 90% particles have particle size less than about 400 microns; 50% particles have particle size less than about 200 microns and 10% particles have particle size less than about 30 microns.
Another embodiment of the present invention provides pharmaceutical composition comprising Lacosamide prepared by the process of the present invention and at least one pharmaceutically acceptable excipient.

Unless otherwise indicated, the following definitions are set forth to illustrate and
define the meaning and scope of the various terms used to describe the invention
herein.
The term "Boc" as used herein refers to t-butoxycarbonyl.
The term "benzylamination" as used herein refers to reaction with ArCH2NH2 in such a
way that the -NH2 moiety can form an amide bond.
The term "substantially free" means Lacosamide having less than about 2%, preferably
less than about 0.5%, more preferably less than about 0.2% of other impurities.
The term "reflux temperature" means the temperature at which the solvent or solvent
system refluxes or boils at atmospheric pressure.
The term "room temperature" should be understood to mean a temperature ranging
from about 20° C to about 40°C.
The term "one-pot" reaction as used herein means reaction in which two or more
processes are conducted in a single reaction vessel without isolating or purifying the
resulting intermediates.
X-ray powder diffraction pattern has been obtained on Xpert'PRO, PANalytical, dif-fractometer equipped with accelerator detector using Copper Kα (λ =1.5406 A) radiation with scanning range between 4-50 2θ at scanning speed of 2o/min.
The following examples illustrate the invention described above, however they are not intended to limit its extent in any manner.
Examples:
Example 1: N-Boc D-serine(III)
To an ice cooled solution of D-serine (64 g, 61 mmol) in IN sodium hydroxide (1.3 L) was added a solution of di-tert-butyl carbonate (156 g, 71 mmol) in 1,4-dioxane (560 mL). The reaction mixture was stirred at room temperature for 4 hours. Potassium bisulphate was added to the reaction mixture till pH of 2-3 was achieved. Ethyl acetate was added to the mixture and the product was extracted in ethyl acetate. The ethyl acetate layer was evaporated to get the product as an oil. Yield 111 g, 89%.

Example 2: 2(R)-N-Boc-amino-N-benzyl-3-hydroxy propionamide (IV)
To a solution of N-Boc D-serine (25 g, 122 mmol) and N-methyl morpholine (12 g, 119 mmol) was added 250 ml of tetrahydrofuran. The reaction mixture was cooled to -30 to - 40°C under nitrogen and then isobutyl chloroformate (14.9g, 109 mmol) was added dropwise to precipitate white solid. The reaction mixture was stirred for 30 min at the same temperature and benzylamine (13.9g, 130mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was filtered to remove N-methyl morpholine hydrochloride and tetrahydrofuran was distilled out completely. Ethyl acetate (1 L) was added to the obtained product. This mixture was then washed or stirred with water (1 L). The organic layer was separated from the aqueous layer. The separated organic layer was dried over anhydrous sodium sulfate and distilled off under reduced pressure to remove ethyl acetate. The residue obtained was further purified using methyl tert butyl ether to get the title compound in solid form. Yield: 26 g, 89 %
1HNMR (400 MHz, DMSO d6): 1.34 (s, 3H, CH3), 3.58 (d, J=3.2 Hz, 2H, CH2-N), 4.08 (d, J=1.6 Hz, 2H), 4.28 (d, 2H), 6.67 (d, J=8.0Hz, -OH), 7.23-7.32(m, 5H, Ar-H), 8.33(s, 1H, CONH).
Example 3: (R)-N-benzyl-2-amino-3-hydroxypropionamide hydrochloride
A solution of 2(R)-N-Boc amino-N-benzyl-3-hydroxypropionamide (26 g, 88 mmol) in isopropanol (450 ml) was added to conc, hydrochloric acid (15 ml) and the reaction mixture was stirred for 1 hour at room temperature. Solvent was removed from the reaction mixture completely under reduced pressure. The obtained residue was treated with methyl tert butyl ether (150 ml) and filtered to get the title compound. Yield: 86.84 g, 60.74% w.r.t D-serine
1'HNMR (400 MHz, DMSO d6): 3.23 (t, 1H, CH), 3.39-3.55 (m, 2H, CH2OH), 4.28 (d, 2H, NHCH2), 4.76 (s, 1H, OH), 7.18-7.32 (m, 5H, Ar-H), 8.34 (s, 2H, NH2), 9.05 (d, NH-amide).
Example 4:(R)-N-benzyl-2-amino-3-hydroxypropionamide hydrochloride
To a mixture of N-Boc-D-serine (1.0 Kg, 4.87mol) and N-methyl morpholine (0.54 Kg, 5.3 mol) was added tetrahydrofuran (10.0 L). The reaction mixture was cooled to -30 to

-40°C under nitrogen and then isobutyl chloroformate (0.73Kg, 5.3mol) was added dropwise to the obtained reaction mixture. The reaction mixture was stirred for 30 min at the same temperature. Benzylamine (0.57 Kg, 5.4 mol) was gradually added to the reaction mixture at the same temperature. The reaction mixture was gradually warmed to 25 to 35° C and stirred for 1 hour. The reaction mixture was filtered to remove N-methyl morpholine hydrochloride. The solvent of the filtrate was distilled out completely under reduced pressure. Ethyl acetate (10.0 L) was added to the residue and washed with aqueous solution of citric acid (0.2 Kg in 10.0 L). The layers were separated. The separated organic layer was dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to get an oily residue which was then treated with mixture of isopropanol (8.0 L) and conc, hydrochloric acid (0.4 L). The reaction mixture was stirred for 1 hour at 50 to 55° C. The solvent was distilled off under reduced pressure and the residue was stirred with methyl tertbutyl ether (10.0 L). The solid obtained was filtered to get (R)-N-benzyl-2-amino-3-hydroxy propionamide hydrochloride. Yield: 0.85Kg, 76%
Example 5:(R)-N-benzyl-2-amino-3-hydroxypropionamide hydrochloride
To a mixture of N-Boc-D-serine (1.0 Kg, 4.9 mol) and N-methyl morpholine (0.54 Kg, 5.3 mol) was added tetrahydrofuran (10.0 L). The reaction mixture was cooled to -5 to 0°C under nitrogen and then pivaloyl chloride (0.61Kg, 5.05 mol) was added dropwise to the obtained reaction mixture. The reaction mixture was stirred for 30 min at the same temperature. Benzylamine (0.57 Kg, 5.3 mol) was gradually added to the reaction mixture at the same temperature. The reaction mixture was gradually warm to 25 to 35° C and stirred for 1 hour. The reaction mixture was filtered to remove N-methyl morpholine hydrochloride. The solvent of the filtrate was distilled out completely under reduced pressure. Ethyl acetate (10.0 L) was added to the residue and washed with aqueous solution of citric acid (0.2 Kg in 10.0 L). The layers were separated. The separated organic layer was dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to get an oily residue which was then treated with mixture of isopropanol (8.0 L) and conc, hydrochloric acid (0.4 L). The reaction mixture was stirred for 1 hour at 50 to 55° C. The solvent was distilled off under

reduced pressure and the residue was stirred with methyl tertbutyl ether (10.0 L). The solid obtained was filtered to get (R)-N-berizyl-2-amino-3-hydroxypropionamide hydrochloride. Yield: 0.65Kg, 58%
Example 6: (R)-N-benzyl-2-amino-3-hydroxypropionamide hydrochloride
To an ice cooled solution of D-serine (64 g, 61 mmol) in IN sodium hydroxide (1.3 L) was added a solution of di-tert-butyl carbonate (156 g, 71 mmol) in 1,4-dioxane (560 ml). The reaction mixture was stirred at room temperature for 4 hours. Potassium bisulphate was added to the reaction mixture till pH of 2-3 was achieved. Ethyl acetate was added to the mixture and the product was extracted in ethyl acetate. Ethyl acetate was evaporated under vacuum to get an oil. Tetrahydrofuran (1.5 L) was added to the oil followed by N-methyl morpholine (60 g, 60 mmol). The reaction mixture was cooled to -30 to - 40°C under nitrogen and then isobutyl chloroformate (74.5g, 55 mmol) was added dropwise to precipitate white solid. The reaction mixture was stirred for 30 min at the same temperature and benzylamine (74.5 g, 69.5 mmol) was added. The mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was filtered to remove N-methyl morpholine hydrochloride and tetrahydrofuran was distilled out completely. Ethyl acetate (5.0 L) was added to the obtained product. This mixture was then washed with water (5.0 L). The organic layer was separated from the aqueous layer. The separated organic layer was dried over anhydrous sodium sulfate and distilled off under reduced pressure to get an oil. Isopropanol (2.25 L) and cone, hydrochloric acid (66 mL) were added to the oily residue and the resultant reaction mixture was stirred for 1 hour at room temperature. Solvent was removed from the reaction mixture completely under reduced pressure. The obtained solid was treated with methyl tert butyl ether (750 ml) and filtered to get the title compound. Yield : 85 gm, 83%
Example 7 :(R)-N-benzyl-2-acetamido hydracrylamide (VI):
Magnesium oxide (6.4 g, 16 mmol) and tetrahydrofuran (200ml) were added to the suspension of (R)-N-benzyl-2-amino-3-hydroxypropionamide hydrochloride (15.6 g, 67.6 mmol) in water. The reaction mixture was cooled to 0-10 °C and acetyl chloride (6.3g, 80.3 mmol) was added dropwise. The solution was gradually warmed to room

temperature and stirred for 2 hours. Solvent was distilled off completely under reduced pressure. The resultant solid obtained was treated with methyl tert butyl ether and filtered to get the title compound. Yield: 13g, 82%
1HNMR(400 MHz, DMSO d6): 1.86 (s, 3H, 0=CCH3), 3.57 (d, 2H, J=5.8Hz, CH2OH), 4.25-4.31 (m, 1H)), 4.27 (d, 2H, J=5.7 Hz, NH), 4.92 (t, 1H), 7.18-7.32 (m, 5H, Ar-H), 7.94 (d, 1H, NH), 8.38 (s, 1H, NH, amide)
Example 8 Preparation of Lacosamide (I):
To a mixture of (R)-N-benzyl-2-acetamido hydracrylamide (13.0g, 55.3mmol), tetrabutyl ammonium bromide (2g) and sodium hydroxide (23.2g, 58 mmol) was added a mixture of water (100ml) and dichloromethane (130.0 ml) followed by addition of dimethyl sulphate (26 g, 20.6 mmol) at 0 to 5°C for 5 hours. The organic layer was separated and washed with water. The organic layer was concentrated to obtain a residue The obtained residue was treated with ethyl acetate to get Lacosamide. Yield: 11 g, 80%, Purity >98%, S-isomer less than 0.15%
'HNMR (400 MHz, CDCI3): 2.04 (s, 3H, 0=C-CH3), 3.38(s, 3H, OMe), 3.44-3.88 (dd, 2H, CH2-OMe) 4.38 (d, 2H, NHCH2), 4.52-4.58(t, 1H), 6.46 (br s, 1H, NH), 6.78 (s, 1H, NH), 7.25-7.37(m, 5H, ArH).
Example 9: Preparation of Lacosamide (I):
To a mixture of (R)-N-benzyl-2-acetamido hydracrylamide (13.0g, 55.3mmol), tetrabutyl ammonium bromide (2g) and sodium hydroxide (23.2g, 58 mmol) was added a mixture of water (100ml) and tetrahydrofuran (130.0 ml) followed by addition of dimethyl sulphate (26.0g, 206 mmol) at 0 to 5°C for 2 hours. Tetrahydrofuran was distilled off under reduced pressure at 25-35°C. The reaction mixture was extracted with dichloromethane (150 ml). The organic layer was separated and washed with water followed by removal of organic layer completely. The obtained residue was treated with ethyl acetate to get Lacosamide. Yield: 12.35 g, 89.68%, Purity >98%.
Example 10: Preparation of Lacosamide (I):
To a mixture of (R)-N-benzyl-2-acetamido hydracrylamide (13.0g, 55.3mmol), tetrabutyl ammonium bromide (2g) and sodium hydroxide (23.2g, 58 mmol), was

added a mixture of water (100ml) and dichloromethane (130.0 ml) followed by addition of methyl iodide (70.97 g, 500 mmol) at room temperature. The reaction mixture was stirred for 12 hours. The organic layer was separated and washed with water followed by distillation of organic layer. The obtained residue was treated with ethyl acetate to get Lacosamide. Yield: 7.8g, 56.64%, Purity >98%
Example 11 Preparation of Lacosamide (I):
Magnesium oxide (6.4 g, 15.9 mmol) and tetrahydrofuran (200 mL) were added to a suspension of (R)-N-benzyl-2-amino 3-hydroxypropionamide hydrochloride (15.6 g, 67.8 mmol) in water (40 mL). The reaction mixture was cooled to 0-10 °C. Acetyl chloride (6.3 g, 80.4 mmol) was added dropwise to the reaction mixture and stirred for 2 hours. The reaction mixture was filtered through hyflow bed. To the filtrate was added tetrabutyl ammonium bromide (2g), sodium hydroxide (23.2 gm, 58 mmol) in 160 mL water followed by addition of dimethyl sulphate (26 g, 206 mmol) at 0-5 °C. The reaction was carried out for about 5 hours The organic solvent was distilled off under reduced pressure at 45-55°C. The reaction mixture was extracted with dichloromethane (150 ml). The organic layer was separated and washed with water followed by complete removal of the organic layer. The obtained residue was treated with ethyl acetate (62 ml) to get Lacosamide. Yield: 9.36 g, 60%, Purity > 9S%.
Example 12:Purification of Lacosamide
10 g of Lacosamide was dissolved in ethyl acetate (150 ml) at reflux temperature of 70-75°C. The clear solution was filtered to remove any insoluble, if present. The filtrate was warmed to 35 to 45°C and stirred at the same temperature for 5 hours. The reaction mixture was gradually cooled to 0-5°C to get solid. The obtained solid was filtered and washed with 10ml cold ethyl acetate and dried at 60-70°C to get Lacosamide. Yield: 8.6g, 86%, Purity> 99.8%, S-isomer less than 0.15%.
Example 13:Purification of Lacosamide
10 g of Lacosamide was dissolved in ethyl acetate (150 ml) at 70-75°C. Methyl tert butyl ether (100 ml) was added to the mixture at 70-75°C. The reaction mixture was gradually cooled to 0-5°C to get solid. The obtained solid was filtered, washed with

20 ml ethyl acetate-methyl tert butyl ether (1:1) and dried at 60-70°C to get Lacosamide. Yield: 9.2 g; 92%, Purity >99.8%
Example 14: Purification of Lacosamide
10 g of Lacosamide was dissolved in tetrahydrofuran (150 ml) at 70-75°C. Hexane (100 ml) was added to the mixture at 70-75°C. The reaction mixture was gradually cooled to 0-5°C to get solid. The obtained solid was filtered, washed with 20 ml tetrahydrofuran-hexane (1:1) and dried at 60-70°C to get Lacosamide. Yield: 9.2 g; 92%, Purity >99.8%
Example 15: Purification of Lacosamide
10 g of Lacosamide was dissolved in acetonitrile (150 ml) at 70-75°C. Methyl tert butyl ether (100 ml) was added to the mixture at 70-75°C. The reaction mixture was gradually cooled to 0-5°C to get solid. The obtained solid was filtered, washed with 20 ml acetonitrile-methyl tert butyl ether (1:1) and dried at 60-70°C to get Lacosamide. Yield: 9.2 g; 92%, Purity >99.8%
Example 16: Purification of Lacosamide
10 g of Lacosamide was dissolved in tetrahydrofuran (150 ml) at 70-75°C. Methyl tert butyl ether (100 ml) was added to the mixture at 70-75°C. The reaction mixture was gradually cooled to 0-5°C to get solid. The obtained solid was filtered, washed with 20 ml tetrahydrofuran-methyl tert butyl ether (1:1) and dried at 60-70°C to get Lacosamide. Yield: 9.2 g; 92%, Purity >99.

We claim,
1. A process for preparation of Lacosamide comprising the steps of,
a) treating (R)-N-benzyl-2-amino-3-hydroxypropionamide or salt thereof with an acetylating agent in presence of metal oxide to get (R)-N-benzyl-2-acetamido hydracrylamide; and
b) converting (R)-N-benzyl-2-acetamido hydracrylamide to Lacosamide.

2. The process as claimed in claim 1, wherein said metal oxide is selected from magnesium oxide, zinc oxide, aluminum oxide, copper oxide or cobalt oxide; and said acetylating agent is selected from acetyl chloride, acetic anhydride or acetic acid.
3. The process as claimed in claim 2, wherein said treatment with acetyl chloride is carried out in presence of tetrahydrofuran-water or 1,4-dioxane-water at a temperature of 0 to 10°C.
4. The process as claimed in claim 1, wherein said (R)-N-benzyl-2-amino-3-hydroxypropionamide is prepared by a process comprising the steps of,

a) benzylaminating N-protected-D-serine in presence of a carbonyl group activator to obtain 2(R)-(N-protected)-amino-N-benzyl-3-hydroxy propionamide;
b) optionally, isolating 2(R)-(N-protected)-amino-N-benzyl-3-hydroxy propionamide; and
c) deprotecting 2(R)-(N-protected)-amino-N-benzyl-3-hydroxy propionamide to obtain (R)-N-benzyI-2-amino-3-hydroxy propionamide or salt thereof.
5. The process as claimed in claim 4, wherein said carbonyl group activator is
isobutyl chloroformate or pivaloyl chloride; said benzylamination is carried out
in the presence of N-methyl morpholine and tetrahydrofuran at a temperature of
-50 to 10°C; and said deprotection is carried out using a mineral acid.

6. The process as claimed in claim 4, wherein said N-protected-D-serine is N-Boc-D-serine prepared by a process comprising treating D-serine with di-tert-butyl dicarbonate.
7. The process as claimed in claim 1, wherein said conversion comprises O-methylation of (R)-N-benzyl-2-acetamido hydracrylamide to obtain Lacosamide.
8. The process as claimed in claim 7, wherein said O-methylation is carried out using dimethyl sulphate in the presence of base selected from sodium hydroxide or potassium hydroxide and phase transfer catalyst selected from tetrapropyl ammonium hydroxide, tetrabutyl ammonium halide such as tetrabutyl ammonium bromide, tetrabutyl ammonium chloride or tetrabutyl ammonium iodide.
9. The process as claimed in claim 7, wherein said treatment with an acetylating agent and said O-methylation is carried out in one-pot.
10. A process for preparation of Lacosamide wherein benzylamination of N-protected-D-serine in presence of a carbonyl group activator to obtain 2(R)-(N-protected)-amino-N-benzyI-3-hydroxy propionamide; deprotection of 2(R)-(N-protected)-amino-N-benzyl-3-hydroxy propionamide to obtain (R)-N-benzyl-2-amino-3-hydroxy propionamide; and acetylation of (R)-N-benzyl-2-amino-3-hydroxypropionamide to (R)-N-benzyl-2-acetamido hydracrylamide is carried out in one-pot.