Field of the invention:

The present invention relates to an improved process for the preparation of (R)-N-benzyl-2-Acetamido-3-methoxypropionamide (commonly known as Lacosamide) represented by the following structural formula-1

Lacosamide is an anticonvulsant drug useful in the treatment of Central Nervous System disorders such as Epilepsy. This Drug is also useful in the treatment of pain particularly neuropathic pain such as Diabetic neuropathic pain. Lacosamide is a functionalized aminoacid. This medication was formerly developed by UCB and sold under the Brand name VIMPAT®.

Background of the Invention:

Lacosamide and process for its preparation was disclosed in US 5773475. Different routes for the preparation of lacosamide have been reported in literature, for example US 5773475, US 6,048,899, US 2008/027137 and US 2009/143472 and Tetrahedron Asymmetry 1998, 9, 3841-3854.

US patent publication US 2008/0027137 disclosed a process for the preparation of (R)-2-((t-butoxy)carbonylamino)3-methoxypropanoic acid and its conversion to lacosamide. The disclosed process involves the protection of D-serine with di-t-butyl dicarbonate to provide N-Boc-D-serine, which is further 0-methylated using dimethylsulphate to provide (R)-2-((t-butoxy)carbonylamino)3-methoxy propanoic acid. Both the protection and 0-methylation reaction were carried in a biphasic solvent system such as in a mixture of toluene & water, in presence of phase transfer catalyst and a base. Even though the disclosed process provides good yield, it involves the usage of costly reagent such as phase transfer catalyst, which increases the cost of production.

It has now surprisingly found by the present inventors that both the protection and 0-methylation reaction has been carried out in a single phase solvent system without using costly phase transfer catalyst with good yields and purity, there by reduces the cost of production. The present invention provides an improved process for the preparation of lacosamide, wherein the o-methylation of N-Boc-D-serine and protection of D-serine with di-t-butyl dicarbonate were carried out in a single phase solvent system without usage of phase transfer catalyst.

Summary of the Invention:

In one embodiment, the present invention provides an improved process for the preparation of (R)-2-(t-butoxycarbonylamino)3-methoxypropanoic acid compound of formula-4, which comprises of 0-methylating the (R)-2-(tert-butyoxycarbonylamino)-3-hydroxypropanoic acid (herein after referred as "N-Boc-D-serine") compound of formula-3 with a suitable methylating agent in the presence of base in a single phase solvent system without usage of a phase transfer catalyst.

In another embodiment, the present invention provides an improved process for the preparation of N-Boc-D-serine compound of formula-3, which comprises of reacting the D-serine with suitable N-protecting reagent in the presence of a base in a single phase system without the usage of phase transfer catalyst.

In another embodiment, the present invention provides an one-pot process for the preparation of lacosamide compound of formula-1 starting from D-serine, where in the protection of D-serine with suitable protecting agent and O-methylation of N-Boc-D-serine was carried out in a single phase system without usage of a phase transfer catalyst.
In another embodiment, the present invention provides novel acid addition salts of (R)-N-benzyl-2-amino-3-methoxypropionamide compound of formula-7, process for its preparation and their use in the synthesis of highly pure compound of formula-6 and lacosamide.

Brief Description of the Drawings:

Figure-1: PXRD pattern of lacosamide prepared as per the present invention
Figure-2: DSC thermogram of lacosamide prepared as per the present invention

Detailed Description of the Invention:

For the purpose of the present invention, as used herein the term "base" refers to the bases selected from "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide and the like; "alkali metal carbonates" such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate and the like;

For the purpose of the present invention, as used herein the term "alcohol solvents" refers to methanol, ethanol, n-propanol, isopropanol and n-butanol and the like; "hydrocarbon solvents" refers to toluene, xylene, cyclohexane, hexane, heptane and the like; "polar aprotic solvents" refers to dimethylsulfoxide, dimethylacetamide, dimethyl formamide, tetrahydrofuran, acetonitrile and the like; "chloro solvents" refers to methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform and the like; "nitrile solvents" refers to acetonitrile and the like;

According to one embodiment, the present invention provides an improved process for the preparation of (R)-2-(t-butoxycarbonylamino)3-methoxypropanoic acid compound of formula-4.

Formula-3 with a suitable methylating agent in the presence of base, in a single phase solvent system without usage of a phase transfer catalyst.

Preferably the suitable methylating agent used is selected from dimethylsulphate or dimethylcorbonate and base is selected from potassium hydroxide, sodium hydroxide, calciumhydroxide and lithiumhydroxide etc,

Preferably the solvent used for single phase system is selected from polar solvents like alcohol solvents such as methanol, ethanol, isopropanol and water, most preferably water and the reaction carried out at a temperature of 0-15°C, preferably 5-10°C.

In a preferred embodiment of the present invention, process for the preparation of (R)-2-(t-butoxycarbonylamino)3-methoxypropanoic acid compound of formula-4 comprises of 0-methylating the N-Boc-D-serine compound of formula-3 with dimethyl sulfate in presence of sodium hydroxide and water at 5-10°C.

In another embodiment, the present invention provides an improved process for the preparation of N-Boc-D-serine compound of formula-3,

Formula-3 which comprises of protecting the D-serine compound of formula-2

Formula-2 with a suitable N-protecting reagent in presence of a base, in a single phase solvent system without the usage of phase transfer catalyst.

Preferably the N-protecting agent is di-t-butyl dicarbonate (DIBOC) and a base used is selected from potassium hydroxide, sodium hydroxide, calciumhydroxide and lithiumhydroxide etc,.

Preferably the solvent used for single phase system is selected from polar solvents like alcohol solvents such as methanol, ethanol, isopropanol and water, most preferably water and the reaction carried out at a temperature of 15-30 °C, preferably 20-25°C.

In a preferred embodiment of the present invention, the process for the preparation of N-Boc-D-serine compound of formula-3 comprises of protecting the D-serine compound of formula-2 with di-t-butyl dicarbonate (DIBOC) in the presence of sodium hydroxide and water at 20-25°C.

In another embodiment, the present invention provides one-pot process for the preparation of lacosamide compound of formula-1. which comprises of reacting the D-serine compoimd of formula-2 with suitable N-protecting reagent, in the presence of a base in a single solvent system without usage of phase transfer catalyst to provide the N-Boc-D-serine compound of formula-3. treating the N-Boc-D-serine compound of formula-3 in-situ with suitable methylating agent in the presence of a suitable base, in a single solvent system without usage of phase transfer catalyst to provide ((R)-2-(t-butoxycarbonylamino)3-methoxypropanoic acid compound of formula-4. and reacting the compound of formula-4 in-situ vdth benzylamine in the presence of ethylchloroformate or isobutylchloroformate and N-methyl morpholine in a suitable chloro solvents selected from methylenechloride, chloroform and carbontetrachloride to provide the (R)-2-tert-butyl-l-(benzylamino)-3-methoxy-l-oxopropan-2-ylcarbonate compound of formula-5, and treating the compound of formula-5 in-situ with a suitable inorganic acid selected from hydrochloric acid, sulphuric acid or phosphoric acid in presence or absence of a solvent to provide the (R)-N-benzyl-2-amino-3-methoxypropionamide compound of formula-6, then reacting the compound of formula-6 in-situ with acetic anhydride at a suitable temperature of 15-25°C, preferably 20-25°C in a suitable chloro solvent selected from methylene chloride, chloroform and carbontetrachloride to provide the lacosamide compound of formula-1, and optionally purifying the lacosamide using a suitable solvent selected from ester solvents such as ethylacetate, ethylbutyrate, isobutylacetate preferably ethylacetate gives highly pure lacosamide compoimd of formula-1.

In a preferred embodiment of the present invention, one-pot process for the preparation of lacosamide comprises of protecting the D-serine compound of formula-2 with di-t-butyl dicarbonate in the presence of sodium hydroxide and water at 20-25°C to provide N-Boc-D-serine compound of formula-3, which on in-situ reaction with dimethyl sulfate in presence of sodium hydroxide and water at 5-10°C to provide (R)-2-(t-butoxycarbonylamino)3-methoxypropanoic acid compound of formula-4, which on in-situ reaction with benzylamine in the presence of ethylchloroformate and N-methyl morpholine in methylene chloride to provide the (R)-2-tert-butyl-l-(benzylamino)-3-methoxy-l-oxopropan-2-ylcarbonate compound of formula-5, which on in-situ treatment with hydrochloric acid to provide the (R)-N-benzyl-2-amino-3-methoxypropionamide compound of formula-ó, which on in-situ treatment with acetic anhydride at 20-25°C to provide the lacosamide compound of formula-l.

In another embodiment, the present invention provides novel acid addition salts of (R)-N-benzyl-2-amino-3-methoxypropionamide represented by the following structural formula-7, wherein "Acid" is a acid which are capable of forming acid addition salt with (R)-N-benzyl-2-amino-3-niethoxypropionamide compound of formula-6 and selected from oxaiic acid, succinic acid, fumaric acid, malonic acid, malic acid, maleic acid, tartaric acid, citric acid, methanesulfonic acid, paratoluene sulfonic acid, acetic acid, sulfuric acid, phosphoric acid and hydrohalic acid. Novel acid addition salts of the present invention are used to prepare highly pure compound of formuIa-6 and lacosamide compound of formula-1.

The (R)-N-benzyl-2-amino-3-methoxypropionamide compound of formula-6 prepared as per the prior art processes having very less purity in the range of 90-92% by HPLC. The present inventors surprisingly found that the purity of the (R)-N-benzyl-2-amino-3-methoxypropionamide can be further enhanced upto 96-98%, by forming its acid addition salts and converting back into free base compound of formula-6. Hence it is advantageous to have high purity intermediate compound of formula-6 and its usage in the preparation of highly pure lacosamide compound of formula-l.

Further the present invention provides a process for the preparation of acid addition salt of (R)-N-benzyl-2-amino-3-methoxypropionamide compound of formula-7, which comprises of reacting the compound of formula-6 with a suitable acid as defined above in a suitable solvent selected from alcoholic solvent, ketone solvent and the like, to provide the corresponding salt compound of formula-7.

Further the present invention provides a process for the preparation of highly pure compound of formula-6, which comprises of treating (R)-N-benzyl-2-amino-3-methoxypropionamide with a suitable acid to provide corresponding salt compound of formula-7 and converting the salt compound of formula-7 into highly pure compound of formula-6 by treating it with suitable base in a suitable solvent, wherein the obtained (R)-N-benzyl-2-amino-3-methoxypropionamide is having high purity than the starting (R)-N-benzyl-2-amino-3-methoxypropionamide.

The highly pure compound of formula-6 further converted into highly pure lacosamide by treating with acetic anhydride in a suitable solvent per the process known in the art.

In a preferred embodiment, the present invention provides oxalic acid salt of (R)-N-benzyl-2-amino-3-methoxypropionamide compound of formula-7a and it's used to prepare highly pure lacosamide compound of formula-1 and formula-6.

In a preferred embodiment, the present invention provides a process for the preparation of (R)-N-benzyl-2-amino-3-methoxypropionamide oxalate salt compound of formula-7a, which comprises of the following steps,
a) Dissolving the compound of formula-6 in isopropyl alcohol,
b) adding a solution of oxalic acid in isopropylalcohol and stirring,
c) cooling the reaction mixture 0-5 °C,
d) raise the temperature to 10-15 °C and stirring,
e) filtering off the solid and washed with isopropyl alcohol,
f) drying the obtained solid to get (R)-N-benzyl-2-amino-3-methoxypropionamide oxalate.

As used herein the present invention the term "highly pure" refers to the purity of the particular compound having purity grater than 95% by High performance liquid chromatography, preferably greater than 97% by HPLC and more preferably greater than 99% by HPLC.

The following impurities are generally formed in the preparation of lacosamide.

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples:

ExampIe-1: Preparation of N-Boc-D-serine of Formula 3:
Di-tert.butyldicarbonate (124.5 grams) was added to solution of D-serine (50 grams) in aqueous sodium hydroxide (38.5 g of NaOH in 250 ml of water) at 20-25°C and stirred for 10 hovirs at 20-25 °C. The reaction mixture containing N-Boc-D-serine has been used directly to next stage with out any purification.

Example-2: Preparation of (R)-2-(tert-butoxycarbonylamino)-3-methoxy propionic acid compound of formula-4:

Sodium hydroxide (19 g) was added to a reaction mixture containing N-Boc-D-serine (430 ml) obtained in example-1 at 0-5°C and stirred for 30 mins. Dimethylsulphate (340 ml) and sodium hydroxide solution (153 g in 152 ml of water) was added reaction mixture slowly over 4 hours at 5-10°Cand then stirred for 10 hrs. The pH of the reaction mass was acidified with dilute hydrochloricacid at 0-5°C. Methylene chloride (100 ml) was added to the reaction mixture and the layers get separated. Aqueous layer was extracted with methylene chloride and the methylene chloride layer containing the title compound was directly used for the next stage without any purification.

Example-3: Preparation of (R)-2-tert-butyl l-(benzylamino)-3-methoxy-l-oxopropan-2-yl carbonate compound of formula-5:

Ethylchoroformate (49.3 g) foliowed by N-methylmorpholine (46 g) was added to a pre-cooled reaction mass of (R)-2-(tert-butoxycarbonylamino)-3-methoxy propionicacid (280 ml) obtained in example-2 at -10 to -15°C and stirred for 15 min at -15°C. Benzylamine (49 g) was added to the reaction mixture slowly at -10 to -15°C and stirred for 1.5 hours. Reaction temperatute was raised to 20-25°C and stirred for 1.5 hours. The reaction mixture was washed with dilute hydrochloric acid (100 ml), and further the organic layer was washed with sodiumnbicarbonate solution followed by washed with water. The reaction mixture containing title compound was directly used for next stage without any isolation and purification.

Example-4:

Preparation of (R)-N-benzyl-2-amino-3-methoxypropionamide compound of formula-6 Concentrated hydrochloric acid (175 ml) was added to a reaction mixture containing (R)-N-Benzyl-2-N'-(tert.butoxycarbonyl)amino-3-methoxy propionamide (280 ml) obtained in expla-3 at 0-5°C and stirred for 3 hrs. The organic and aqueous layers were separated. Aqueous layer was basified with sodium hydroxide and the reaction mixture extracted into methylene chloride. The methylene chloride layer containing the title compound used directly in the next step without any further isolation or purification.

Example-5: Preparation of lacosamide compound of formula-1:

Acetic anhydride (48.5 g) was added to methylene chloride layer containing (R)-N-benzyl-2-amino-3-methoxypropionamide (390 ml) obtained in example-4 at 20-25 °C and stirred for an hour. The reaction mixture was washed with sodium carbonate solution followed by water, and the solvent from the reaction mixture was distilled off under atmospheric pressure. Ethyl acetate (50 ml) was added to the residue and distilled off it completely. Ethyl acetate (250 ml) was added to the obtained residue and heated to 75 -80°C, stirred for 30 minutes and filtered through high-low. The filtrate was cooled to 55-60°C and stirred for 4 hours. The reaction mixture was further cooled to 0-5° and stirred for 1 hr. The solid obtained was filtered off and washed with ethyl acetate. Ethyl acetate was added to the wet solid and heated to 75-80°C and stirred for 45 min at 75-80°C. The reaction mixture was cooled to 20-25°C and stirred for 1.30 hrs. The solid obtained was filtered off, and washed with ethyl acetate and dried to get the title compound. Yield: 65 grams

Purity by HPLC: 99.86%; o-actyl impurity: 0.05%; acetamide impurity: 0.05%; amino impurity: Not detected; hydroxyl impurity: 0.01%

Example-6: Preparation of (R)-N-benzyl-2-amino-3-methoxypropionamide oxalate compound of formula-7a:

A solution of oxalic acid (2.1 grams) in isopropyl alcohol (5 ml) was added to a solution of (R)-N-benzyl-2-amino-3-methoxypropionamide having purity of 91.8% (5 grams) in isopropyl alcohol(10 ml) at 25-32°C and stirred for 15 minutes. The reaction mixture was cooled to 0-5° and stirred for 30 min. Then the reaction mixture was stirred for 30 minutes at 10-15°C. The solid obtained was filtered, washed with isopropyl alcohol and dried to get the title compound. Yield: 2.5 grams Purity by HPLC: 97%

Example-7:

Preparation of highly pure (R)-N-benzyl-2-ammo-3-methoxy propionamide compound of formula-6:

Water (10 ml) was added to (R)-N-benzyl-2-amino-3-methoxy propionamide oxalate compound of formula-7a (1 grams) and the reaction mixture was basified with sodium hydroxide solution. Extracted the reaction with methylene chloride and distilled off the methylene chloride layer to get the title compound. Yield: 0.6 grams Purity by HPLC: 96.8%

We claim:

1. A process for the preparation of (R)-2-(t-butoxycarbonylamino)3-methoxypropanoic acid compound of formula-4,

Formula-4

which comprises of 0-methylating the N-Boc-D-serine compound of formula-3

Formula-3

with a suitable methylating agent in the presence of base in a single phase solvent system without usage of a phase transfer catalyst.

2. A process for the preparation of N-Boc-D-serine compound of formuIa-3,
Formula-3 which comprises of protecting the D-serine compound of formula-2
Formula-2 with suitable N-protecting reagent in the presence of a base in a single phase solvent system without the usage of phase transfer catalyst.

3. A process according to claim 1 or 2, wherein the base used is selected from sodium hydroxide, potassium hydroxide and lithium hydroxide and the single phase solvent used is water.

4. A process according to claim-1, wherein the suitable methylating agent is selected from dimethysulphate and dimethylcorbonate.

5. A process according to claim 2, wherein the N-protecting agent used is di-t-butyl dicarbonate (DIBOC).

6. An improved process for the preparation of lacosamide, characterized in that 0-methylation of N-Boc-D-serine compound of formula-3 and protection of D-serine with N-protecting agent has been carried out in a single phase solvent system and with out usage of a phase transfer catalyst.

7. One-pot process for the preparation of lacosamide compound of formula-1,

Formula-1

which comprises of reacting the D-serine compound of formula-2 with suitable N-protecting reagents in the presence of a base in a single solvent system without usage of phase transfer catalyst to provide the N-Boc-D-serine compound of formula-3,

Formula-3

treating the N-Boc-D-serine compound of formula-3 in-situ with suitable methylating agent in the presence of a suitable base in a single solvent system without usage of phase transfer catalyst to provide ((R)-2-(t-butoxycarbonylamino)3-methoxypropanoic acid compound of formula-4,

and reacting the compound of formuia-4 in-situ with benzylamine in presence of ethylchloroformate or isobutylchloroformate and N-methyl morpholine in a suitable chloro solvents selected from methylenechloride, chloroform and carbontetrachloride to provide the (R)-2-tert-butyl-l-(benzylamino)-3-methoxy-l-oxopropan-2-ylcarbonate compound of formula-5,

Formula-5

and treating the compound of fonnula-5 in-situ with a suitable inorganic acid selected from hydrochloric acid, sulphuric acid or phosphoric acid in presence or absence of a solvent to provide the (R)-N-benzyl-2-amino-3-methoxypropionamide compound of formula-6.

Formula-6

then reacting the compound of formula-6 in-situ with acetic anhydride at a suitable temperature of 15-25°C, preferably 20-25°C in a suitable chloro solvent selected from methylene chloride, chloroform and carbontetrachloride to provide the lacosamide compound of formula-1, and optionally purifying the lacosamide using a suitable solvent selected from ester solvents such as ethylacetate, ethylbutyrate, isobutylacetate preferably ethylacetate gives highly pure lacosamide compound of formula-1.

8. Acid addition salts of (R)-N-benzyl-2-amino-3-methoxypropionamide represented by the following structural formula-7.

wherein "Acid" is a acid which are capable of forming acid addition salt with (R)-N-benzyl-2-amino-3-methoxypropionamide compound of formula-6 and selected from oxalic acid, succinic acid, fumaric acid, malonic acid, malic acid, maleic acid, tartaric acid, citric acid, methanesulfonic acid, paratoluene sulfonic acid, acetic acid, sulfuric acid, phosphoric acid and hydrohalic acid.

9. A process for the preparation of acid addition salt of (R)-N-benzyl-2-amino-3-methoxypropionamide compound of formula-7 of claim 8, which comprises of reacting the (R)-N-benzyl-2-amino-3-methoxypropionamide compound of formula-6 with a suitable acid as defined in claim 8 in a suitable solvent selected from alcoholic solvent and ketone solvent provides the corresponding salt compound of formula-7.

10. Use of (R)-N-benzyl-2-amino-3-methoxypropionamide acid addition salts compound of formula-7 in the preparation of highly pure (R)-N-benzyl-2-amino-3-methoxypropionamide compound of formula-6 and lacosamide compound of formula-1.