WO2013024383A1

WO2013024383A1 - An improved process for the preparation of lacosamide

Info

Publication number: WO2013024383A1
Application number: PCT/IB2012/053875
Authority: WO
Inventors: Venkatraman JAYARAMAN; Bijukumar Gopinathan Pillai; Bhavinkumar HAMIRANI
Original assignee: Alembic Pharmaceuticals Limited
Priority date: 2011-08-12
Filing date: 2012-07-30
Publication date: 2013-02-21

Abstract

The present invention relates to an improved process for the preparation of Lacosamide having formula (I).

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF LACOSAMIDE

Field of the invention

Background of the invention

Lacosamide (R)-2-acetamido-N-benzyl-3 methoxypropionamide , has the following formula:

It is a drug that has been used in the treatment of epilepsy. Lacosamide is marketed under the trade name Vimpat(R) by UCB. It was approved by the FDA as an adjunctive therapy for partial-onset seizures in October 2008.

U.S. Patent No. 5,654,301 discloses certain compounds which are amino acid derivatives and includes lacosamide. Various synthetic schemes for the preparation of these derivatives are disclosed.

Lacosamide and its methods of preparation are disclosed in U.S. Reissue Patent No. RE 38,551. The patent provides three general methods for the preparation of lacosamide. The first two methods do not involve the protection of active groups in intermediate compounds (such as amino, hydroxy and carboxylic acid groups). The other method disclosed in this patent involves protection of an amino group present in D-serine with carbobenzoxy chloride (Cbz-Cl), subsequent O-methylation at the hydroxy group followed by amidation at carboxylic (-COOH) acid with benzylamine and finally removal of the 'Cbz' group followed by acetylation, to produce lacosamide.

An alternative method for the preparation of lacosamide is disclosed in International (PCT) Publication No. WO 2006/037574 that involves O-methylation of N- Boc-protected-D-serine ('Boc' refers to t-butoxycarbonyl) directly in one step by avoiding simultaneous formation of the methyl ester moiety.

US 20090143472 disclose certain intermediates and methods of preparation of lacosamide using the intermediates. The process of preparation of lacosamide involves O- methylation of the intermediate, benzyl amine amidation, detritylation and finally acetylation to yield lacosamide. Another method disclosed involves first benzyl amine amidation of the intermediate, and then O-methylation, subsequently followed by detritylation and finally acetylation.

WO2010052011 discloses the resolution of 2-acetamido-N-benzyl-3- methoxypropionamide using chiral chromatography.

In view of the preparation methods available for lacosamide, there is a need for simple and cost effective processes for the preparation of lacosamide that provides improved efficiency per reaction volume in terms of yield and purity, including both chemically and chirally.

Object of the invention

It is therefore an object of the present invention is to provide an improved process for the preparation Lacosamide.

Another object of the present invention is to provide an improved process for the preparation of Lacosamide which is operationally simple, easy to handle and applicable at an industrial scale.

Yet another object of the present invention is to provide process for the preparation of Lacosamide comprising steps of:

condensing N-Boc-D-serine with benzyl amine to obtain (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- hydroxypropionamide
treating (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- hydroxypropionamide with phase transfer catalyst in presence of base & methylating agent to obtain (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- methoxypropionamide
deprotecting (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- methoxypropionamide in presence of conc. HCl & MDC to obtain (R)-2- amino-N-benzyl-3- methoxypropionamide
treating (R)-2- amino-N-benzyl-3- methoxypropionamide with acetic anhydride in presence of MDC to obtain crude Lacosamide
treating crude Lacosamide in presence of solvent to obtain pure Lacosamide

Another object of the present invention is to provide an improved process for the preparation of Lacosamide comprising a step of:

treating (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- hydroxypropionamide with phase transfer catalyst in presence of base & methylating agent to obtain (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- methoxypropionamide.

Summary of the invention

In the present aspect of the invention, it provides an improved process for the preparation of Lacosamide comprising steps of:

condensing N-Boc-D-serine with benzyl amine to obtain (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- hydroxypropionamide;
treating (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- hydroxypropionamide with phase transfer catalyst in presence of base & methylating agent to obtain (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- methoxypropionamide;
deprotecting (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- methoxypropionamide in presence of conc. HCl & MDC to obtain (R)-2- amino-N-benzyl-3- methoxypropionamide;
treating (R)-2- amino-N-benzyl-3- methoxypropionamide with acetic anhydride in presence of MDC to obtain crude Lacosamide;
treating crude Lacosamide in presence of solvent to obtain pure Lacosamide.

Another aspect of the present invention is to provide an improved process for the preparation of Lacosamide comprising a step of:

Brief Description Of The Drawings:

Fig. I shows the X-ray powder diffraction pattern of crystalline Form I prepared by prior art process.

Fig. II shows the X-ray powder diffraction pattern of crystalline Form I of Lacosamide obtained by the present invention.

Detail description of the invention

The present embodiment provides an improved process for the preparation of Lacosamide comprising steps of:

Another embodiment of the present invention is to provide an improved process for the preparation of Lacosamide comprising a step of:

The term 'treating' as used hereinabove refers to suspending, dissolving or mixing and contacting or reacting of product with solvent or reagents followed by isolating product by removal of reagents and solvents.

Suitable phase transfer catalysts are tetraethylammonium p- toluenesulfonate, tetrapropylammonium trifluoromethanesulfonate, tetraphenylphosphonium hexafluoroantimonate, cetylpyridinium bromide, triphenylmethyl triphenylphosponium chloride, benzyltriethylammonium chloride, benzyltrimethylammonium chloride, benzyltriphenylphosphonium chloride, benzytributylammonium chloride, butyltriethylammonium bromide, butyltriphenylphosphonium bromide, cetyltri methyl ammonium bromide, cetyltri methyl ammonium chloride, ethyltriphenylphosphonium bromide, ethyltriphenylphosphonium iodide, methyltrioctylammonium bromide, methyltriphenylphosphonium bromide, methyltriphenylphosphonium iodide, phenyltrimethylammonium chloride, tetrabutylammonium 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, tetraphenylphosphonium bromide, tetrapropylammonium hydroxide, tetrapropylammonium bromide and tributylmethylammonium chloride, wherein tetrabutylammonium salts and particularly tetrabutylammonium halides, e.g. the bromide are especially preferred.

Suitable methylation agents are e.g. dimethyl sulphate, trimethyl phosphate or methyl iodide with dimethyl sulphate being particularly preferred.

Base is selected from the group comprising like alkali or alkaline earth metal hydroxide, alkali or alkaline carbonate, alkali or alkaline bicarbonate, organolithium, organomagnesium compounds, organic base and the like or mixtures thereof. Alkali or alkaline earth metal hydroxide, alkali or alkaline carbonate, alkali or alkaline bicarbonate used herein above are selected from NaOH, KOH, LiOH, NaHCO₃, KHCO₃, LiHCO₃, Na₂CO₃, K₂CO₃, Li₂CO₃, Mg(OH)₂, Ca(OH)₂, CaCO₃, MgCO₃, Ba(OH)₂, Be(OH)₂, BaCO₃, SrCO₃, (CH₃)₃COK and the like or mixtures thereof. Organolithium used herein above are selected from n-BuLi, sec-BuLi, t-BuLi, MeLi, PhLi. Organomagnesium used herein above are selected from phenylmagnesium bromide, ethylmagnesium bromide. Organic base used herein above are selected from nitrogen containing base such as pyridine, piperidine, dimethyl amino pyridine, picolines, diisopropyl ethyl amine, triethyl amine and the like or mixtures thereof.

Suitable solvent is selected from a group comprising ketones, nitriles, acetates, aromatic hydrocarbons, alcohol, ether, alkanes and the like or mixtures thereof. Ketones used herein above are selected from methyl ethyl ketone, acetone, methyl isobutyl ketone, 3-heptanone. Acetates used herein above are selected from isopropyl acetate, ethyl acetate, methyl acetate, n-butyl acetate, t-butyl acetate. Nitriles used herein above are selected from acetonitrile, benzonitrile. Aromatic hydrocarbons used herein above are selected from toluene, xylene. Alcohols used herein above are selected from C1-C4 linear or nonlinear. Ethers used herein above are selected from diethyl ether, dimethyl ether, THF & dioxane. Alkanes used herein above are selected form any of the C1-C10 compounds.

The general reaction scheme is as follow:

It is an applicants observation that when Lacosamide is prepared according to WO2006037574A1 (Example 4) it produces crystalline Form I. This Form I is characterized by XRD reflections (peak) at about 6.8, 8.5, 10.7, 13.3, 15.8, 16.9, 17.8, 21.7, 25.2, 25.6 & 27.3 ±0.2 degrees 2θ. In summary Form I is resulted by preparing the prior art process as disclosed in WO2006037574A1 (Example 4).

Applicants has also obtained the same crystalline form I of Lacosamide by following the present improved process of Lacosamide. This form I is characterized by XRD reflections (peaks) at about 6.6, 8.4, 10.5, 13.1, 15.7, 16.7, 17.7, 21.5, 25.1, 25.4 & 27.3 ±0.2 degrees 2θ.

The XRD's characterizing of the lacosamide polymorphs as described herein were obtained using the X-pert-PRO RDAD-1044.

In the following section, aspects are described by way of examples to illustrate the process of the invention & product thereof. However, the examples mentioned below are not intended in any way to limit the scope of the present invention. Several variants of these examples would be evident to persons ordinarily skilled in the art.

Process for the preparation of Lacosamide

Step-1 Preparation of (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- hydroxypropionamide

Charged the N-Boc-D-serine (200 gm) with MDC (600ml) followed by cooling the reaction mass at R.T. Add N-methyl morpholine (108.44 g) at-35±5°C in the obtained reaction mass followed by addition of methyl chloroformate (101.31 g) at-35±5°C.in minimum 25-30min. Stirred the reaction mass for approximate 30 min. Add prechilled solution of benzyl amine in MDC (5-10°C) in to the obtained reaction mass in minimum 25-30min at R.T. Stirred the reaction mass for 25-30 min followed by addition of process water (600 ml) at 27±3°C and layers formed were separated. The organic layer was washed with de-ionized water. Layers were separated and solvent was recovered from the organic layer to obtain crude material. Charged cyclohexane (1400 ml) at below 60°C. Cool the reaction mass at R.T followed by stirring the reaction mass for 2-3 hrs at same temperature. Filter the solid and wash it with cyclohexane (200 ml) at 27±3°C. Drying under vacuum at 47±3°C gave title compound.

Step-2 Preparation of tert-butyl [(2R)-1-(benzylamino)-3-methoxy-1-oxopropan-2- yl] carbamate

Reaction mass of Stage II (190 g), toluene (950 ml), NaOH (71 g in 380ml of process water) (~415ml) and tetrabutyl ammonium bromide (35.36 g) were added at 27±3°C. Cooled the reaction mass to 2±3°C and the solution was stirred for 5-10 min. at 2±3°C and dimethyl sulfate (162.8 g) was added at 2±3°C followed by stirring for 5-10 min. at 2±3°C. Raised the temperature of reaction mass to 27±3°C and then it was stirred for 90 min. at the same temperature. The layers were separated. The organic layer was collected. The aqueous layer was extracted with toluene (190 ml), stirred and allowed to settle. The combined organic layers were washed with 5% w/v sodium bicarbonate solution (47.5 g in 950 ml). The organic layer was collected and distilled out toluene completely under vacuum at below 56°C to obtained residue. Cyclohexane (190 ml) was added to residue at below 56°C and distilled out cyclohexane completely under vacuum at below 56°C. Degas the residue for 1-2 hr under vacuum (720 mm/Hg) at below 56°C. Cyclohexane (380 ml) was added to residue at below 56°C. Cooled the reaction mass to 27±3°C and then it was stirred for 2-3 hr. at the same temperature. Solid was filtered and washed with cyclohexane (190 ml) at 27±3°C. The solid was dried under vacuum at 47±3°C.

Step-3 Preparation of (2R)-2-amino-N-benzyl-3-methoxypropanamide

Step II reaction mass (145 gm), dichloromethane (725 ml) and HCl (217.5 ml) were added at 27±3°C and stirred the reaction mass for 80-90 min. at 27±3°C. DM water was added 27±3°C and stirred for 5-10 min. at 27±3°C. The layers were separated. The organic layer was collected. The organic layer was washed with 10% v/v HCl solution (29ml con HCl make 290 ml using DM water), stirred at 27±3°C for 5-10 min and allowed to settle. The combined aqueous layer was cooled to 0-5°C. Adjust pH 9-10 using 20%w/v Sodium hydroxide solution at 0-15°C. Dichloromethane (725 ml) was added at 10-25°C and stirred for 5-10 min. at 27±3°C. The layers were separated. The organic layer was collected. The aqueous layer was extracted with dichloromethane (2×290 ml), stirred at 27±3°C and allowed to settle and layers were separated. Combined organic layers and sodium chloride solution (65.25g in 435ml DM water) was added at 27±3°C and stirred for 10-15 min. at 27±3°C. The layers were separated. The organic layer (Product is in organic layer) was collected.

Step-4 Preparation of (2R)-2-(acetylamino)-N-benzyl-3-methoxypropanamide (crystalline Form I)

To the organic layer (dichloromethane layer) obtained as above, acetic anhydride (57.55 g) was added at 27±3°C and stirred for 30 min. at 27±3°C. DM water (290 ml) was added 27±3°C and stirred for 5-10 min. at same temperature. The layers were separated. The organic layer was collected. The organic layer was washed with 5% w/v sodium bicarbonate solution (14.5g in 290 ml DM water), stirred at 27±3°C and allowed to settle. The organic layer was collected. The organic layer was washed with DM water, stirred at 27±3°C and allowed to settle. The organic layer was collected. Activated carbon was added 27±3°C and stirred for 30 min. at 27±3°C. Filtered the reaction mass through hyflow bed and washed the bed with dichloromethane (145 ml). Filtrate was collected. Distilled out dichloromethane at below 50°C atmospherically, Isopropyl alcohol was added at 47±3°C and stirred for 5-10 min. Distilled out Isopropyl alcohol under vacuum at 47±3°C. Isopropyl alcohol (290 ml) was added at 47±3°C and the reaction was heated at 81±3°C followed by addition of n-heptane (1450 ml) at same temperature. Stir the reaction mass for 15-20 min. at the same temperature. Cooled the reaction mass to 40±3°C and stirred for 8 hr. at the same temperature. Cooled the reaction mass to 3±3°C and stirred for 30 min. at the same temperature. Solid was filtered at 3±3°C and washed with n-heptane (145 ml) at 27±3°C. The solid was dried in vaccum at 42±3°C for 6-8 hr.

Claims

An improved process for the preparation of Lacosamide comprising steps of :

i) condensing N-Boc-D-serine with benzyl amine to obtain (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- hydroxypropionamide;

ii) treating (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- hydroxypropionamide with TBAB as a phase transfer catalyst in presence of NaOH & DMS as a methylating agent to obtain (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- methoxypropionamide;

iii) deprotecting (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- methoxypropionamide in presence of conc. HCl & MDC to obtain (R)-2- amino-N-benzyl-3- methoxypropionamide;

iv) treating (R)-2- amino-N-benzyl-3- methoxypropionamide with acetic anhydride in presence of MDC to obtain crude Lacosamide;

v) treating crude Lacosamide in presence of mix. of isopropyl alcohol and n-heptane to obtain pure Lacosamide.
An improved process for the preparation of Lacosamide comprising a step of :

treating (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- hydroxypropionamide with TBAB as a phase transfer catalyst in presence of NaOH & DMS as a methylating agent to obtain (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- methoxypropionamide.