FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"AN IMPROVED PROCESS FOR THE PREPARATION OF LACOSAM1DE"
Enaltec Labs Pvt Ltd. an Indian Company, having its Registered Office at 17th Floor, Kesar Solitaire, Plot No.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India. Pin Code: 400705
1. The following specification particularly describes the invention and the manner in which it is to be performed.

AN IMPROVED PROCESS FOR THE PREPARATION OF LACOSAMIDE
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of lacosamide compound of structural formula I, wherein N-Boc-protected-D-serine ("Boc" refers to t-butoxycarbonyl functional group) compound of structural formula XII is benzylated to produce a compound of structural formula XIX, which on methylation, deprotection and acylation produces lacosamide compound of structural formula I.

BACKGROUND OF THE INVENTION
Lacosamide is chemically (R)-2-acetamido-N-benzyl-3-methoxypropionamide and is known from U.S Patent No. RE 38,551 and is represented by formula I.

Lacosamide is indicated for partial-onset seizures in patients with epilepsy aged 17 years and older.

U.S Patent no. RE 38,551 provides three methods for the preparation of lacosamide. The first method involves benzylation of D-serine compound of structural formula II to produce a compound of structural formula IV, which on acylation and 0-methylation produces lacosamide compound of structural formula I as described below in scheme no. I.

The second method involves the acylation of D-serine compound of structural formula II to produce a compound of structural formula VI, which on benzylation and O-methylation produces lacosamide compound of structural formula I as described below in scheme no. II.


The third method involves the protection of an amino group present in D-serine compound of structural formula II with carbobenzoxy chloride (Cbz-Cl) to get a compound of structural formula VII, which on methylation with methyl iodide gives a compound of structural formula VIII, which on hydrolysis, benzylation, deprotection and acylation produces lacosamide compound of structural formula I as described below in scheme no.III.


U.S Patent publication no. 2008/0027137 describes a process for the preparation of lacosamide compound of structural formula I that involves O-methylation of N-Boc-protected-D-serine ("Boc" refers to t-butoxycarbonyl functional group) compound of structural formula XII with dimethyl sulfate in the presence of phase transfer catalyst to produce a compound of structural formula XIII, which on benzylation, deprotection and acylation yields lacosamide compound of structural formula 1 as described below in scheme no. IV. This process avoids the simultaneous formation of methyl ester moiety.


U.S Patent publication no. 2009/0143472 describes two processes for the preparation of lacosamide compound of structural formula 1 wherein first process involves O-methylation of trityl protected-D-serine ("Trityl" refers to triphenyl methyl functional group) compound of structural formula XV to produce a compound of structural formula XVI, which on benzylation, detritylation and acylation yields lacosamide compound of structural formula I as described below in scheme no. V.

Second process involves benzylation of trityl protected-D-serine ("Trityl" refers to triphenyl methyl functional group) compound of structural formula XV to produce a compound of formula XVIII, which on methylation, detritylation and acetylation yields lacosamide compound of formula I as described below in scheme no. VI.


The prior art processes for preparing iacosamide compound of structural formula I are not commercially viable due to formation of lot of impurities along with Iacosamide. The purification of which resulted into low yield of pure Iacosamide compound of structural formula 1 and therefore there is a need in the art to develop an improved process for the preparation of Iacosamide compound of structural formula I, which produces high yield of Iacosamide compound of structural formula I.
SUMMARY OF THE INVENTION
A first aspect of the present invention is to provide a commercial viable process for the preparation of Iacosamide, which obviates the prior a.rt problems.
A second aspect of the present invention is to provide an improved process for the preparation of Iacosamide compound of structural formula 1 as described below in scheme no. VII.


A third aspect of the present invention is to provide an improve process for the preparation of lacosamide by methylating a compound of formula XIX.

Formula XIX
A fourth aspect of the present invention is to provide a novel intermediate of formula XIX.

A fifth aspect of the present invention is to provide a process for the preparation of substantially pure lacosamide compound of formula 1.
The "substantially pure lacosamide" compound refers to the lacosamide having more than 99% purity by HPLC.
Another aspect of the present invention is to provide an improved process of preparing lacosamide compound of structural formula 1 comprising the steps of:
a. benzylation of N-Boc-protected-D-serine ("Boc" refers to t-butoxycarbonyl
functional group) compound of structural formula XII to produce a compound
of structural formula XIX.


b. O-methylation of compound of structural formula XIX t0 prociuce a compound of structural formula XIV,

Kormula XIX
l-'ormulaXlV
c. deprotection of compound of structural formula XIV t0 produce a compound of structural formula XI and,

Kormula XIV
f-ormula XI
d. acylation of compound of structural formula XI to yields lacosamide compound of structural formula I.


DETAIL DESCRIPTION OF THE INVENTION
The protection of D-serine compound of structural formula II may be carried out with Boc-anhydride.
The reaction of D-serine compound of structural formula il with Boc-anhydride may be carried out in an ether solvent at a temperature in the range of 0°C to 30°C for a period of 6 hours to 24 hours to produce a compound of structural formula XJI.
The examples of ether solvents may include but not limited to tetrahydrofuran, 2-methyl tetrahydrofuran, 1, 4-dioxane, methyl tertiary butyl ether, diethyl ether, diisobutyl ether, di-n-butyl ether, di-n-propyl ether, diisopropyl ether or mixture(s) thereof.
The reaction of D-serine compound of structural formula II with Boc-anhydride may be carried out in the presence of an aqueous solution of an inorganic base.
The examples of an inorganic base may include but not limited to sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.
N-Boc-protected-D-serine compound of structural formula XII may be isolated by quenching the reaction mixture with an aqueous solution of hydrochloric acid
followed by the extraction with an alkyi acetate solvents and concentration under reduced pressure.
The pH of above mentioned quenching solution may be in the range of 2 to 3.
The benzylation of N-Boc-protected-D-serine ("Boc" refers to t-butoxycarbonyl functional group) compound of structural formula XII may be carried out by reacting a compound of structural formula XII with alkyi chloroformate in the presence of organic base, followed by the reacting resulting mixed anhydride compound of structural formula XX with benzyl amine.


The examples of alkyl chloroformate may include but not limited to ethyl chloroformate, isobutyl chloroformate, n-butyl chloroformate or methyl chloroformate.
The benzylation of N-Boc-protected-D-serine ("Boc" refers to t-butoxycarbonyl functional group) compound of structural formula XII may be carried out by reacting a compound of structural formula XII with isobutyl chloroformate in the presence of organic base, followed by the reacting resulting mixed anhydride compound of structural formula XX with benzyl amine.

The examples of organic base may include but not limited to triethyl amine, diisopropyl amine, 1, 8-diazabiicyclo [5.4.0] undec-7-ene, N-methyl morpholine
The reaction of N-Boc-protected-D-serine ("Boc" refers to t-butoxycarbonyl functional group) compound of structural formula XII with isobutyl chloroformate may be carried out in halogenated hydrocarbons solvent at a temperature in the range of -20°C to 30°C for a period of 2 hours to 8 hours to produce a mixed anhydride compound of structural formula XX.

The examples of halogenated hydrocarbon solvents may include but not limited to dichloromethane, dichloroethane, carbon tetrachloride, chloroform or mixture(s)
thereof.
The mixed anhydride compound of structural formula XX may be isolated or used as such for the further step of reaction.
The mixed anhydride compound of structural formula XX may be reacted with benzyl amine at a temperature in the range of -15°C to 30°C for a period of 3 hours to 8 hours to produce a compound of structural formula XIX.
The compound of structural formula XIX may be isolated by quenching the reaction mixture with water followed by the separation of an organic layer.
The organic layer containing the compound of structural formula XIX may be washed with IN HC1 solution and an aqueous solution of sodium bicarbonate.
The aqueous solution of sodium bicarbonate may have concentration in the range of 5% weight / weight to 10% weight /weight.
The organic layer containing the compound of structural formula XIX may be concentrate under reduced pressure to get a compound of structural formula XIX.
The methylation of compound of structural formula XIX may be carried out by dimethyl sulfate, trimethyl phosphate or methyl iodide at a temperature in the range of 0°C to 15°C for a period of 3 hours to 7 hours to get a compound of structural formula XIV.
The methylation of compound of structural formula XIX may be carried out in the presence of phase transfer catalyst in aromatic hydrocarbon solvents.
The examples of phase transfer catalyst may include but not limited to
tetraethylammonium p-toluenesulfonate, tetrapropylammonium

trifluoromethanesulfonate, tetraphenytphosphonium hexafluoroantimonate,
cetylpyridinium bromide, triphenylmethyl triphenylphosponium chloride,
benzyltriethylammonium chloride, benzyltrimethylammonium chloride,
benzyltriphenylphosphonium chloride, benzytributylammonium chloride,
butyltriethylammonium bromide, butyltriphenylphosphonium bromide, cetyltrimethyl
ammonium bromide, cetyltrimethyl ammonium chloride, ethyltriphenylphosphonium
bromide, ethyltriphenylphosphonium iodide, methyltrioctylammonium bromide;
methyltriphenylphosphonium bromide, methyltriphenylphosphonium iodide,
phenyltrimethylamrnonium chloride, tetrabuty [ammonium hydroxide,
tetrabutylammonium perchlorate, tetrabutylammonium bromide, tetrabutylammonium
hydrogensulphate, tetrabutylammonium iodide, tetrabutylammonium
tetrafluoroborate, tetrabutylammonium thiocyanate, tetraethylammonium hydroxide,
tetraethylammonium iodide, tetraethylammonium bromide, tetramethylammonium
chloride, tetramethylammonium iodide, tetramethylammonium chloride,
tetraoctylammonium bromide, tetraphenytphosphonium bromide,
tetrapropylammonium hydroxide, tetrapropylammonium bromide or tributylmethylammonium chloride.
The examples of aromatic hydrocarbon solvents may include but not limited to benzene, toluene, cresol or xylene.
The compound of structural formula XIV may be isolated by quenching the reaction mixture with water followed by the separation of an organic layer.
The organic layer containing the compound of structural formula XIV may be washed with IN HC1 solution and an aqueous solution of sodium bicarbonate.
The aqueous solution of sodium bicarbonate may have concentration in the range of 5% weight / weight to 10% weight / weight.
The organic layer containing the compound of structural formula XIV may be concentrate under reduced pressure to get a compound of structural formula XIV.

The deprotection of compound of structural formula XIV may be carried out by an inorganic acid in above mentioned halogenated hydrocarbon solvents at a temperature in the range of 20°C to 30°C for a period of 2 hours to 4 hours to get a compound of structural formula XI.
The examples of an inorganic acid may include but not limited to hydrochloric acid or hydrobromic acid.
The compound of structural formula XI may be isolated by quenching the reaction mixture with water followed by the separation of an aqueous layer containing the hydrochloride salt of compound of structural formula XI.
The aqueous layer may be further washed with halogenated hydrocarbon solvents.
The pH of aqueous layer may be adjusted in the range of 10-12 by an aqueous solution of alkali metal hydroxide and then it may be extracted with above mentioned halogenated hydrocarbon solvents.
The examples of an alkali metal hydroxide may include sodium hydroxide or potassium hydroxide.
The organic layer containing the compound of structural formula XI may be concentrated under reduced pressure to get crude compound of structural formula XI.
The acylation of compound of structural formula XI may be carried out by acetic anhydride or acetyl chloride in above mentioned halogenated hydrocarbon solvents.
The acylation of compound of structural formula XI may be carried at a temperature in the range of 0°C to 30°C for a period of 3 hours to 12 hours to get a lacosamide compound of structural formula I.
The lacosamide compound of structural formula 1 may be isolated by quenching the reaction mixture with water, followed by separating organic layer.

The organic layer containing the lacosamide compound of structural formula I may be washed with an aqueous solution of sodium bicarbonate and with water.
The organic layer containing the lacosamide compound of structural formula I may be concentrated under reduced pressure to get a residue of lacosamide compound of structural formula 1.
The residue of lacosamide compound of structural formula I may be crystallized by an alkyl acetate solvent to get pure lacosamide compound of structural formula I.
The examples of alkyl acetate solvents may include methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or mixture(s) thereof.
The pure lacosamide compound of structural formula I having more than 99% purity as determined by HPLC technique.
The pure lacosamide compound of structural formula 1 may be dried at a temperature in the range of 50°C to 60°C for a period of 4 hours to 18 hours under reduced pressure.

EXAMPLES
In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example: Preparation of substantially pure lacosamide.
Step-1: Preparation of N-Boc-protected-D-serine compound of structural formula XII D-serine (lOOgm) was added into the aqueous solution of sodium hydroxide [sodium hydroxide (80 gm) dissolved in water (2000 ml)] at 0°C to 5°C and then the solution of Boc-anhydride (270 gm) in 1,4- dioxane (380ml) was added dropwise in 3 hours at 0°C to 5°C. The resulting reaction mixture was first stirred 30 minutes at 0-5°C and then it was stirred for 14 hours at 25-30°C. The reaction mixture was quenched with hydrochloric acid [20% aqueous solution, 550 ml] and then extracted with an ethyl acetate (500ml). The ethyl acetate layer was concentrated under reduced pressure to get title compound Yield: 205gm Purity: 99.87% (By HPLC)
Step-2: Preparation of (R)-tert-butyl ]-(benzylamino)-3-hydroxy-l-oxopropan-2-ylcarbamate compound structural formula XIX
The solution of N-Boc-protected-D-serine compound of structural formula X1J (200gm) in dichloromethane (1600ml) was added isobutyl chloroformate (113.2gm) and N-methyl morpholine (85gm) at -5°C to -10°C. The resulting reaction mixture was stirred for 30 minutes at 0 to -5°C and then the solution of benzyl amine (93gm) in dichloromethane (400ml) was added in 2 hours at 0 to -5°C and then the resulting reaction mixture was first stirred 30 minutes at 0-5°C and then it was stirred for 3 hours at 20-25°C. The reaction mixture was quenched with water (320ml) and organic layer was separated. The organic layer was washed with HC1 solution (IN, 325ml), sodium bicarbonate solution (8% weight/weight, 320ml) and water (320ml). The organic \ayer was dried over anhydrous sodium sulphate (25gm) and concentrated under reduced pressure to get title compound.

Yield: 275gm
Purity: 99.86% (By HPLC)
Step 3: Preparation of (R)-tert-butyl l-(benzylamino)-3-methoxy-l-oxopropan-2-ylcarbamate compound of structural formula XIV
A solution of (R)-tert-butyl I-(benzylamino)-3-hydroxyM-oxopropan-2-y[carbamate compound structural formula XIX (245gm) in toluene (1225ml) was added tetrabutyl ammonium bromide (1 lgm) and sodium hydroxide solution (20%, 136.5ml) at 0-5°C. The resulting reaction mixture was stirred for 30minutes at 5-10°C and then sodium hydroxide solution (50%, 200m)) and dimethyl sulphate (420gm) was added at 5-10°C. The resulting reaction mixture was stirred 14 hours at 5-10°C and then it was quenched with water (600ml). The organic layer was separated and washed with hydrochloric acid solution (IN, 600ml); sodium bicarbonate solution (8% weight/weight, 600ml) and water (600ml). The organic layer was dried over anhydrous sodium sulphate (35gm) and concentrated under reduced pressure to get title compound. Yield: 250gm Purity: 99.94% (By HPLC)
Step 4: Preparation of (R)-2-amino-N-benzyl-3-methoxypropanamide compound of structural formula XL
A solution of (R)-tert-butyl l-(benzylamino)-3-methoxy-l-oxopropan-2-ylcarbamate compound of structural formula XIV (206gm) in dichloromethane (1050ml) was added concentrated hydrochloric acid (33% weight/weight, 250ml) at 25-30°C. The resulting reaction mixture was stirred for 90 minutes at 25-30°C. The aqueous layer was separated, washed with dichloromethane (2x270ml) and then the pH of aqueous layer was adjusted to 12 with sodium hydroxide solution (30%weight/vveight, 400ml). The aqueous layer was extracted with dichloromethane, dried over anhydrous sodium sulphate (40gm) and concentrated under reduced pressure to get title compound Yield: 130gm Purity: 99.90% (By HPLC)

Step 5: Preparation of lacosamide compound of structural formula 1
A solution of (R)-2-amino-N-benzyl-3-methoxypropanamide compound of structural
formula XJ (106gm) in dichloromethane (530ml) was added acetic anhydride (46gm)
at 5-10°C temperature and then the resulting reaction mixture was stirred for 4 hours
at 20-25°C. The reaction mixture was quenched with water (190ml) and organic layer
was separated. The organic layer was washed with sodium bicarbonate solution (8%
weight/weight. 190ml) and water (190ml). The organic layer was dried over
anhydrous sodium sulphate (35gm) and concentrated under reduced pressure to get a
residue. The residue was crystallized in an ethyl acetate solvent (530ml) to get a title
compound.
Yield: 125gm
Purity: 99.99% (By HPLC)

WE CLAIM:
1. An improved process of preparing lacosamide compound of structural formula I comprising the steps of:
a. benzylation of N-Boc-protected-D-serine ("Boc" refers to t-butoxycarbonyl
functional group) compound of structural formula XII to produce a compound
of structural formula XIX.

b. O-methylation of compound of structural formula XIX to produce a compound of structural formula XIV,

c. deprotection of compound of structural formula XIV to produce a compound of structural formula XI and,


d. acylation of compound of structural formula XI to yields lacosamide compound of structural formula I.

2. The process according to claim no. 1 wherein the benzylation of N-Boc-protected-D-serine ("Boc" refers to t-butoxycarbonyl functional group) compound of structural formula XII is carried out by reacting a compound of structural formula XII with alky] chloroformate in the presence of organic base, followed by the reacting resulting mixed anhydride compound of structural formula XX with benzyl amine.

3. The process according to claim no. 2 wherein alkyl chloroformate is selected from the group comprising of methyl chloroformate, ethyl chloroformate, isobutyl chloroformate or n-buty! chloroformate and organic base is selected from the group

comprising of triethyl amine, diisopropyl amine, 1, 8-diazabiicyclo [5.4.0] undec-7-ene, N-methyl morpholine.
4. The process according to claim no. I wherein methylation of compound of structural formula XIX is carried out by methylating agents selected from the group comprising of dimethyl sulfate, trimethyl phosphate or methyl iodide at a temperature in the range of 0°C to 15°C for a period of 3 hours to 7 hours to get a compound of structural formula XIV.
5. The process according to claim no. 1 wherein deprotection of compound of structural formula XIV is carried out by an inorganic acid in halogenated hydrocarbon solvents at a temperature in the range of 20°C to 30°C for a period of 2 hours to 4 hours to get a compound of structural formula XI.
6. The process according to claim no. 5 wherein inorganic acid is selected from the group comprising of hydrochloric acid or hydrobromic acid and halogenated hydrocarbon solvents is selected from the group comprising of dichloromethane; dichloroethane, carbon tetrachloride, chloroform or mixture(s) thereof.
7. The process according to claim no. 1 wherein acylation of compound of structural formula XI is carried out by acetylating agent selected from the group comprising of acetic anhydride or acetyl chloride in halogenated hydrocarbon solvents at a temperature in the range of 0°C to 30°C for a period of 3 hours to 12 hours to get a lacosamide compound of structural formula I.
8. The compound of structural formula XIX

9. A use of compound of structural formula XIX for the preparation of lacosamide compound of structural formula I.
10. A process for the preparation of lacosamide compound of structural formula I by methylation, deprotection of t-butoxycarbonyl functional group and acetylation of compound of structural formula XIX.