Method for preparing lacosamide

Abstract

The present invention provides a novel method for preparing lacosamide with high chiral purity from D-serine. The method of the present invention can obtain lacosamide with high chiral purity in a high yield through a simple and environmentally-friendly process and thus can be easily applied to mass production.

Claims

1. A method for preparing lacosamide of Formula 1: ##STR00003## wherein Bn represents a benzyl group, the method comprising: preparing a compound of Formula 3: ##STR00004## by reacting a compound of Formula 2: ##STR00005## with a methylating agent in the presence of an inorganic lithium compound and only water as a solvent; and preparing the lacosamide of Formula 1 by reacting the compound of Formula 3 with benzylamine.

2. The method of claim 1, wherein the preparing of the compound of Formula 3 comprises: adding the inorganic lithium compound to an aqueous solution containing the compound of Formula 2; and adding the methylating agent after the addition of the inorganic lithium compound.

3. The method of claim 1, wherein the methylating agent is dimethylsulfate.

4. The method of claim 1, wherein the compound of Formula 2 is prepared by reacting D-serine with acetic anhydride.

5. The method of claim 4, wherein the reacting D-serine with acetic anhydride uses a mixture of water and C1-C3 alcohol as a solvent.

6. The method of claim 4, wherein the reacting D-serine and acetic anhydride is carried out in the presence of at least one compound selected from the group consisting of sodium hydrogen carbonate and potassium hydrogen carbonate.

7. The method of claim 1, wherein the inorganic lithium compound is lithium hydroxide (LiOH) or a hydrate thereof.

8. The method of claim 1, wherein the reacting the compound of Formula 3 with benzylamine is carried out in the presence of isobutylchloroformate and a base.

9. The method of claim 1, wherein the reacting the compound of Formula 3 with benzylamine comprises: preparing a mixture containing the compound of Formula 3, isobutylchloroformate and a base; and preparing a reaction solution by adding benzylamine to the mixture.

10. The method of claim 9, further comprising stirring the reaction solution.

11. The method of claim 9, wherein the preparing the mixture and the reaction solution are carried out at −20° C. to −5° C.

12. The method of claim 9, wherein the base comprises at least one base selected from the group consisting of 4-methylmorpholine, triethylamine, and pyridine.

Description

MODE FOR INVENTION

(1) Hereinafter, preferred examples will be described for a better understanding of the present invention. However, the following examples are provided for illustrative purpose only, and are not intended to limit the scope of the present invention.

(2) Moreover, unless otherwise states, the reagents and solvents mentioned below were purchased from Sigma-Aldrich Korea, HPLC was performed with 1200 Series (Agilent Technologies), 1H NMR was recorded on an Oxford NMR 300 MHz spectrometer (Varian Mercury Instrument). The purity and chiral purity was determined by area percentage of HPLC.

Example 1

Preparation of (R)-2-acetamido-3-hydroxypropanoic acid (the Compound Represented by Formula 2)

(3) D-serine (5 g, 0.0476 mole) was suspended and stirred in a mixed solvent of 25 ml of methanol and 25 ml of purified water, and then sodium hydrogen carbonate (12 g, 0.1428 mole) was added at a room temperature, and acetic anhydride (Ac.sub.2O, 10.8 ml, 0.114 mole) was slowly added. The resulting solution was stirred at a room temperature for 30 minutes, and after the completion of the reaction, the reaction solvent was removed by concentration under reduced pressure. Then, 20 ml of purified water was added, and a 1 N aqueous solution of hydrochloric acid was added to adjust the pH to 3. After 100 ml of ethanol was added to the concentrated residue and stirred, the resulting solid was removed by filtration, and the filtrate was concentrated to yield quantitatively (R)-2-acetamido-3-hydroxypropanoic acid as a crude acetyl-D-serine.

(4) .sup.1H-NMR (DMSO) δ (ppm) 7.37 (d, 1H) 3.75 (q, 1H) 3.50 (dd, 1H) 3.28 (dd, 1H) 1.82 (s, 3H)

Example 2

Preparation of (R)-2-acetamido-3-methoxypropanoic acid (the Compound Represented by Formula 3)

(5) (R)-2-acetamido-3-hydroxypropanoic acid (the compound represented by Formula 2) (7 g, 0.0476 mole) was dissolved in 60 ml of purified water and cooled to 0 to 10° C. Then, a 20 wt % aqueous solution of lithium hydroxide monohydrate (10 g, 0.238 mole) was added dropwise while maintaining the temperature, and the resulting solution was stirred for 20 minutes. After dimethylsulfate (13.6 ml, 0.1428 mole) was added dropwise at the same temperature in three divided portions every 30 minutes, the resulting mixture was stirred at the same temperature for 3 hours, and then heated to room temperature (20 to 25° C.). Upon the completion of the reaction after stirring for 2 hours, the filtration was performed and then the filtrate was washed with 50 ml of methylenechloride, and the aqueous phase was separated. After the separated aqueous phase was cooled below 10° C., 3 N aqueous solution of hydrochloric acid was added to adjust the pH to 2.5 to 3, followed by concentration under a reduced pressure. The concentrated residue was suspended in 150 ml of ethyl acetate and filtered, and the filtrate was concentrated to yield the target product in the form of syrup. The yield was 84.1%.

(6) .sup.1H-NMR (DMSO) δ (ppm) 8.15 (d, 1H) 4.38 (m, 1H) 3.58˜3.63 (dd, 1H) 3.45˜3.49 (dd, 1H) 3.23 (s, 3H) 1.84 (s, 3H)

Example 3

Preparation of lacosamide, (R)-2-acetamido-N-benzyl-3-methoxypropionamide (the Compound Represented by Formula 1)

(7) (R)-2-acetamido-3-methoxypropanoic acid (the compound represented by Formula 3) (13 g, 0.081 mole) was dissolved in 260 ml of tetrahydrofuran and cooled below −15° C., and isobutylchloroformate (IBC, 11.1 ml, 0.085 mole) was added and stirred for 10 minutes. 4-methylmorpholine (NMM, 9.3 ml, 0.089 mole) was added dropwise while maintaining the temperature below −10° C., and benzylamine (BnNH.sub.2) was added at the same temperature. The resulting mixture was kept at −15° C. to −10° C. for 1 hour, heated to a room temperature, and then stirred for 3 hours. The reaction solvent was removed by concentration, and the extraction was performed by adding 130 mL of methylenechloride and 13 ml of purified water. The aqueous phase was re-extracted with 60 ml methylenechloride and combined with the organic phase. A separate organic phase was washed sequentially with 100 ml of a 2 wt % aqueous solution of hydrochloric acid, 100 ml of a 2 wt % aqueous solution of sodium hydrogen carbonate, and 10 wt % brine, respectively, to separate an organic phase. Then, the separate organic phase was concentrated under reduced pressure. After ethyl acetate (130 ml) was added to the concentrated residue, the concentrated residue was dissolved by heating the resulting mixture to 60° C., and normal heptane (130 ml) was slowly added. Then, the reactant was cooled to a room temperature and stirred for 2 hours, and the resulting solid was filtered and dried to yield 11 g of lacosamide (I).

(8) Yield: 55%; purity 99.7%; and chiral purity: 100%

(9) .sup.1H-NMR (DMSO) δ (ppm) 8.45 (t, 1H) 8.07 (d, 1H) 7.23 (m, 5H) 4.49 (m, 1H) 4.24 (dd, 2H) 3.5 (m, 2H) 3.25 (s, 3H) 1.87 (s, 3H)

INDUSTRIAL APPLICABILITY

(10) As described above, the present invention provides an environmentally-friendly and economic method for preparing lacosamide which can perform the O-methylation of D-serine with high chiral purity without the use of toxic organic solvent, catalyst, etc.