FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
Complete Specification
[See Sections 10 and rule 13]

Title: Process For The Preparation Of (R)-2-Acetylamino-N-benzyl-3-methoxy-propionamide

Applicant: (a) INTAS Pharmaceuticals Limited
(b) Company Registered under Indian Company ACT
(c) 2nd Floor, Chinubhai Centre,
Ashram Road,
Ahmedabad 380009
Gujarat, India

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 process for preparation of Lacosamide. The process involves deprotection of intermediate (R)-N-benzyl-2-N-(benzyloxycarbonyl) amino-3-hydroxypropionamide to obtain (R)-N-benzyl-2-amino-3-hydroxypropionamide followed by acetylation and O- methylation to obtain lacosamide.

BACKGROUND OF THE INVENTION

Lacosamide (I) is a medication for the adjunctive treatment of partial-onset seizures and diabetic neuropathic pain and is marketed under the trade name Vimpat.

(I)

Lacosamide is a functionalized amino acid that has activity in the maximal electroshock seizure test, like antiepileptic drugs that are believed to act through voltage-gated sodium channels.

Lacosamide was first disclosed in US 5,654,301 (hereinafter referred as ‘301). Its preparation is disclosed in ‘301, US 5,773,475, US 6,048,899 and various other patents. The process for preparing lacosamide generally involves steps given in following scheme:

The process can be carried out without protection of active groups of intermediate but it is advisable to proceed with protection–deprotection strategy to obtain specific and desired isomers. The protection of active groups during synthesis increases the selectivity of methylation. The above processes involve Ag2O as a base in methylation of –OH group. Use of silver oxide and methyl iodide for methylation of –OH group of leads to racemization and also these are very expensive reagents.

WO 2006/037574 discloses use of dimethyl sulfate in presence of phase transfer catalyst for O-methylation of following compound

Wherein R is a protecting group, the methylated compound thus obtained is further used in synthesis of lacosamide.
Process disclosed in US 2009/0143472 uses trityl protection for compound of formula (II). Process disclosed in WO 2010/107993 includes methylation of following compound

in the presence of dimethyl sulphate. In view of the preparation methods available for lacosamide, there is a need for simple and cost effective process for the preparation of lacosamide that eliminates racemization of intermediate compounds and final product and provides improved yield and quality.

OBJECTS OF THE INVENTION

The main objective of the present invention is to provide a process for preparation of pure Lacosamide.

Another object of the invention is to provide simple and cost effective process for the preparation of Lacosamide.

SUMMARY OF THE INVENTION

Thus the present invention provides a process for preparation of lacosamide comprising the steps disclosed in following scheme:

Step (I) of process comprises deprotection of intermediate (R)-N-benzyl-2- amino-3-hydroxypropionamide of formula (IV); followed by step II which comprises acetylation of amino group intermediate of formula (VI) and finally step III comprising methylation of compound of formula (VII) to obtain lacosamide (I).

DETAILED DESCRIPTION

The term lacosamide as used herein refers to R-enantiomeric form of 2-acetamido-N-benzyl-3-methoxypropionamide. The term O-methylation as used herein refers to converting -OH group into an –OCH3 group in a given chemical compound.

Accordingly in an embodiment, the present application provides a process for deprotection of compound of formula (IV). The deprotection (removal of protecting group such as carbobenzyloxy chloride (CBZ) or benzyl chloroformate group) in present process can be performed using deprotecting agent such as palladium on charcoal. The solvent used for deprotection reaction can be selected form alcohol such as methanol, ether solvents like 2-methyl THF, THF and ester like ethyl acetate. The deprotection can be performed under pressure. The reaction can be performed at ambient temperature, under cooling or at heating.
Preferably the deprotection reaction is carried out at ambient temperature. After completion of reaction the reaction mixture can be filtered to remove catalyst and the compound of formula (VI) can be isolated by removal of solvent from filtrate. The solvent can be removed by any conventionally known method.

The compound of formula (VI) is taken for acetylation i.e. conversion of NH2 group to NH-CO-CH3. The acetylation can be carried out at cooling or the ambient temperature. Preferably initially the temperature is maintained below 10 °C and can be raised later to a suitable temperature. The acetylation reaction comprises mixing compound of formula (VI), methylene chloride and acetylating reagent which in present case is preferably acetic anhydride however any suitable acetylating reagent can be used for this purpose. The reaction can be carried out for 15 minutes to 5 hours. Generally the reaction gets completed in about 2-3 hours. The product can be separated by filtration or any other similar technique known in the art.

The O-methylation i.e. converting –OH group of compound of formula (VII) into O-CH3 can be carried out in presence of methylating agent, base, and solvent. The suitable methylating agent can be selected form dimethyl sulphate, methyl iodide or like.

The base used for methylation may include one or more of alkaline or aqueous alkali metal hydroxide such as sodium hydroxide. The reaction is suitably carried out in presence of single base but if desired the reaction can also be carried out in presence of mixture of bases such as sodium hydroxide and silver oxide.

The solvent used for O-methylation can be selected from class of ketone or ether solvents. Suitable ketonic solvents include but not limited to acetone, methylethyl ketone, suitable ether solvents are like tetrahydrofuran, 2-methyl tetrahydrofuran, more preferably acetone is used for this purpose.

The reaction can be carried out under cooling or at ambient temperature. Preferably the reaction is carried out at or below 20 °C more preferably below 10 °C. After completion of reaction the product i.e. Lacosamide can be isolated by separating the organic layer and followed by removal of solvent. The pH of residue obtained after removal of solvent can be adjusted to separate lacosamide (I). The pH can be adjusted to 7-8 by using any base.

Optionally the O-methylation can also be carried out in presence of phase transfer catalyst such as tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium chloride or like; preferably tetrabutylammonium bromide is used.

The starting material used in the present process i.e. compound of formula (IV) can be prepared by the process given in example 1-2 of present application or by any method known in the art.

EXAMPLES

The above said invention can be illustrated by but not limited to following example(s).

Example 1 - Preparation of (R)-N-(Benzyloxycarbonyl) serine

D-serine (50g) was dissolved in water (850ml), to this MgO (60g) and diethyl ether (400ml) was added. The reaction mixture thus obtained was cooled to 0-5 °C followed by slow drop wise addition of benzylchloroformate (50% in toluene, 209ml), After completion of addition the reaction mixture was stirred at the same temperature for 2 hours and then the temperature was raised to ambient temperature. Reaction mixture was stirred at ambient temperature for 45 minutes and then filtered, the aqueous layer was cooled to 0 °C and its pH was adjusted to 3-3.5 by using hydrochloric acid. The reaction mass thus obtained was extracted with ethyl acetate (250ml×4). Solvent was distilled of from organic layer to obtain 90g of title product.

Example 2 - Preparation of (R)-N-Benzyl-2-N-(Benzyloxycarbonyl) amino-3- hydroxypropionamide

Compound of formula (III) (25g) was mixed with 320ml tetrahydrofuran and the reaction mixture thus obtained was cooled below 0 °C followed by addition of isobutyl chloroformate (16.9ml) and benzyl amine (14.3ml). The temperature of reaction mixture was increased to room temperature i.e. 25-30 °C and was stirred at the same for 1.5 hours. After completion the reaction mixture was filtered and the solvent was distilled of from the filtrate. Diethyl ether (150ml) was added to the residue thus obtained followed by filtration of reaction mixture to obtain 27.5g of title compound (IV).

Example 3 - Preparation of (R)-N-Benzyl-2- amino-3-hydroxypropionamide

15g compound of formula (IV) was mixed with methanol (250ml) and to the mixture 1.5g of 10% Pd/C was added. The reaction mixture was stirred at room temperature in presence of hydrogen gas for about 1.5 hours. After completion; reaction mixture was filtered and the solvent was distilled of from the filtrate to obtain 8g of title compound (VI).

Example 4 - Preparation of (R)-N-Benzyl-2-acetamido-3-hydroxy propionamide

10 g of compound of formula (VI) was mixed with methylene chloride (120ml), the mixture thus obtained was cooled to 0-5 °C and stirred at the same for 30-40 minutes. The temperature of reaction mixture was raised to ambient temperature i.e. 25-30 °C and stirred at the same for 30-40 minutes. The reaction mixture was again cooled to 0-5 °C and stirred at the same for 45 minutes, followed by filtration to obtain 8g of the title compound (VII) as solid.

Example 5 - Preparation of lacosamide (I)

To 1g of compound of formula (VII), acetone (25ml) and dimethyl sulfate (2.9ml) were added and the mixture thus obtained was cooled to 0-5 °C. To this sodium hydroxide (2.5ml) was added slowly, and the resulting reaction mixture was stirred at the same temperature for 4-5 hours. After completion of reaction the two layers were separated and solvent was distilled of from organic layer. The pH of residue obtained after distillation of solvent was adjusted to 7-8 by addition of sodium bicarbonate after pH adjustment 25 ml of di-isopropyl ether was added and the resulting mixture was stirred for 30 minutes at ambient temperature. The title product was separated by filtration and dried under vacuum to obtain 0.7g of lacosamide.

Yield = 66%,

Example 7 - Preparation of Lacosamide (I)

To 1g of compound of formula (VII), acetone (25ml), tetrabutylammonium bromide (0.1g) and dimethyl sulfate (2.9ml) were added and the mixture thus obtained was cooled to 0-5 °C. To this aqueous sodium hydroxide solution (0.42g +1.4ml) was added slowly, and the resulting reaction mixture was stirred at the same temperature for 4-5 hours. After completion of reaction the two layers were separated, solvent was distilled off from organic layer. After distillation of solvent water (4ml) was added to the residue and the resultant mixture was extracted with dichloromethane, solvent from organic layer was distilled off and to the residue methyl tertiary butyl ether (6ml) was added, the title product was separated by filtration and dried under vacuum to obtain 0.7g of lacosamide.

Example 8 - Preparation of Lacosamide (I)

To 1g of compound of formula (VII), acetone (25ml), silver oxide (0.05g) and dimethyl sulphate (2.9ml) were added and the mixture thus obtained was cooled to 0-5 °C. To this aqueous sodium hydroxide solution (0.42g +1.4ml) was added slowly, and the resulting reaction mixture was stirred at the same temperature for 4-5 hours. After completion of reaction the two layers were separated, silver oxide was removed by filtration solvent was distilled off from organic layer. After distillation of solvent water (4ml) was added to the residue and the resultant mixture was extracted with dichloromethane, solvent from organic layer was distilled off and to the residue methyl tertiary butyl ether (6ml) was added, the title product was separated by filtration and dried under vacuum to obtain 0.7g of lacosamide.

We Claim:

1. A process to prepare lacosamide of formula (I),

comprising the steps of:
a. deprotection of a compound of formula (IV ),

to obtain a compound of formula (VI),

b. acetylating the compound of formula (VI) to obtain a compound of formula (VII)

c. O-methylating the compound of formula (VII) in presence of base and solvent to obtain lacosamide (I)
2. A process as claimed in claim 1, wherein the O-methylation is carried out in presence of methylating agent selected from dimethyl sulphate, methyl iodide, methyl chloride, methyl bromide or mixtures thereof.

3. A process as claimed in claim 1, wherein the base used in O-methylation is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, silver oxide or mixture thereof.

4. A process as claimed in claim 1, wherein the O-methylation is carried out in presence of solvent selected from ketone, ether, nitrile, ester or mixture thereof.

5. A process as claimed in claim 1, wherein the O-methylation is optionally carried out in presence of phase transfer catalyst selected from tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide or mixture thereof.