Process for preparing lacosamide

Abstract

The present invention provides a process for the preparation of lacosamide in substantially optically pure form, which in one aspect comprises the following steps: (i) resolution of O-methyl-D,L-serine to provide O-methyl-D-serine in substantially optically pure form; (ii) acetylation of O-methyl-D-serine thereby obtained to provide the N-acetyl 10 derivative thereof in substantially optically pure form; (iii) activating the carboxy group of the compound thereby obtained; and (iv) reacting the compound thereby obtained with benzylamine.

Claims

1. A process for the preparation of lacosamide of formula (I): ##STR00018## in at least 95% optically pure form, which process comprises, (ii) acetylating O-methyl-D-serine of formula (III), ##STR00019## to provide the compound of formula (IV), ##STR00020## in at least 95% optically pure form; (iii) activating the carboxy group of the compound of formula (IV) thereby obtained to provide a compound of formula (V), ##STR00021## wherein Q.sup.1 is a carboxy activating group; and (iv) reacting the compound of formula (V) thereby obtained with benzylamine.

2. The process as claimed in claim 1 wherein, in part (ii), the acetylation reaction is effected by treating compound (III) with acetic anhydride in a mixture of tetrahydrofuran and water.

3. The process as claimed in claim 2 wherein the ratio of tetrahydrofuran to water is in the region of 6:1 parts by volume.

4. The process as claimed in claim 1 wherein Q.sup.1 represents isobutoxycarbonyloxy.

5. The process as claimed in claim 1 wherein, in part (iv), the reaction between compound (V) and benzylamine is effected in tetrahydrofuran at a low temperature; followed by quenching with an acidic solution at a low temperature.

6. The reaction product of the process as claimed in claim 1 containing up to 1% of the compound of formula (XVI): ##STR00022##

Description

EXAMPLE 1

O-Methyl-D-serine (Method 1)

(1) Into a 250 mL round-bottomed flask equipped with a stirrer, reflux condenser and thermometer was added O-methyl-D,L-serine (5 g) in 90:10 methanol/water (25 mL). N-Acetyl-D-phenylalanine (8.70 g) was added in one portion and the mixture heated to 50 C. overnight. The suspension was cooled to room temperature and filtered, and the solid was rinsed with 90:10 methanol/water (5 mL) and dried at 40 C. under vacuum for 3 h. The N-acetyl-D-phenylalanine salt of O-methyl-D-serine (3.4 g, 25%) was obtained as a white solid with a chiral purity >90%. Regeneration of the title compound could be effected by adjustment of the pH to 1-2 by treatment with HCl, followed by extraction into an organic solvent and subsequent adjustment of the pH to 7 with NaOH.

EXAMPLE 2

O-Methyl-D-Serine (Method 2)

(2) Into a 250 mL round-bottomed flask equipped with a stirrer, reflux condenser and thermometer was added O-methyl-D,L-serine (5 g) in ethanol (150 mL). N-Acetyl-(R)-naphthylalanine (10.80 g) was added in one portion and the mixture heated to 50 C. overnight. The suspension was cooled to room temperature and filtered, and the solid was rinsed with ethanol (5 mL) and dried at 40 C. under vacuum for 3 h. Crude N-acetyl-(R)-naphthylalanine salt of O-methyl-D-serine (6.4 g, 40.5%) was obtained as a white solid with a chiral purity >90%. A portion (5 g) of this solid was suspended in ethanol (30 mL), heated to 50 C. for 4 h, cooled to room temperature and filtered. The resulting solid was rinsed with ethanol (5 mL) and dried at 40 C. under vacuum for 3 h. Pure N-acetyl-(R)-naphthylalanine salt of O-methyl-D-serine (4.6 g, 91.5%) was obtained as a white solid with a chiral purity >95%. Regeneration of the title compound could be effected by adjustment of the pH to 1-2 by treatment with HCl, followed by extraction into an organic solvent and subsequent adjustment of the pH to 7 with NaOH.

EXAMPLE 3

O-Methyl-D,L-Serine Benzyl Ester

(3) To a slurry of D,L-serine (500 g, 4.76 mol) in 1,4-dioxane (2.5 L) at 0-5 C. was slowly added a solution of sodium hydroxide (400 g, 10 mol) in water (2.5 L), followed by dicarbonate (1639 mL, 7.14 mol). The temperature was then raised to 25-27 C., and the reaction mixture was maintained at that temperature overnight. The solvent was evaporated under reduced pressure to approximately one-third of the total reaction mass, then the reaction mixture was filtered through Celite to remove the salts. The aqueous layer was washed with ethyl acetate (22.5 L), cooled to 0-5 C., then acidified with a solution of citric acid (4.4 kg, 23.15 mol) in water (3.6 L), and the pH was adjusted to 2. The residue was extracted with ethyl acetate (52.5 L), then the combined organic layers were washed with brine (1 L) and dried over sodium sulphate. The solvent was evaporated under reduced pressure to afford a pale yellow viscous liquid (925 g, 94.7%). HPLC purity: 78.03%.

(4) To a mixture of this material (500 g, 2.4 mol) in toluene (2.5 L) was added tetrabutylammonium bromide (39.2 g). The reaction mixture was cooled to 0-5 C., then dimethyl sulphate (946.5 mL, 9.7 mol) and a solution of sodium hydroxide (878 g, 21.9 mol) in water (2.17 L) were simultaneously added at 0-5 C. The reaction mixture was maintained at 0-5 C. for 30 minutes, then the temperature was raised to 25-27 C. and the reaction mixture was maintained at that temperature overnight. The reaction mixture was allowed to settle, and separated into two layers. The aqueous layer was washed with toluene (2.5 L), cooled to 0-5 C., then acidified with a solution of citric acid (1.85 kg, 9.7 mol) in water (1.34 L), to pH 3 at 0-5 C. The residue was extracted with dichloromethane (62.5 L), then the combined organic layers were washed with brine (1.8 L) and dried over sodium sulphate. The solvent was evaporated under vacuum to afford an off-white solid (281 g, 52.6%). HPLC purity: 81.1%.

(5) To a mixture of this material (385 g, 1.75 mol) in acetone (1925 mL) was added potassium carbonate (358 g, 2.6 mol) slowly at 0-5 C., followed by slow addition of benzyl bromide (210 mL, 1.75 mmol). The temperature was maintained at 0-5 C. for 30 minutes, then raised to 25-27 C. and the reaction mixture was maintained at that temperature overnight. The reaction mass was filtered to remove the inorganic salts, and the salts were then washed with acetone. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate. The ethyl acetate layer was washed twice with water, followed by brine. The organic layer was dried over sodium sulphate. The solvent was evaporated completely to provide a brick red-coloured liquid (540 g, 98.7%).

(6) To a mixture of this material (300 g, 0.97 mol) in tetrahydrofuran (1.5 L) at 0-5 C. was slowly added a solution of conc. hydrochloric acid (793 mL) in water (1.6 L). The temperature was maintained at 0-5 C. for 30 minutes, then raised to 25-27 C. and the reaction mixture was maintained at that temperature for 30 h. The solvent was evaporated completely and the aqueous layer was washed five times with dichloromethane. The aqueous layer was basified (pH 10) with sodium carbonate (700 g) at 0-5 C. The residue was extracted four times into dichloromethane, and the organic layer was dried over sodium sulphate. The solvent was evaporated completely under vacuum to afford the title compound (122 g, 60%) as a pale yellow liquid. HPLC purity: 95.17%.

EXAMPLE 4

O-Methyl-D-Serine (Method 3)

(7) To a solution of O-methyl-D,L-serine benzyl ester (50 mg, 0.239 mol) in 4-methyl-2-pentanone (500 mL) was added N-acetyl-L-methionine (45.7 g, 0.239 mol) at 25 C. The reaction mixture was heated to 50 C. and stirred for 2 hours, then allowed to cool to 25 C. and stirred for 16 hours at 25-30 C. The resulting solid material was filtered and dried at 60 C. for 3 hours. The mother liquors were evaporated. The isolated solid material (66 g) was dissolved in water (132 mL) at 25 C. The aqueous solution was basified with aqueous Na.sub.2CO.sub.3 solution (1M; 0.28 mol) at 5-10 C. The reaction mixture was extracted with dichloromethane (3330 mL) at 25-30 C. The organic layer was dried over Na.sub.2SO.sub.4 and the solvent was evaporated under reduced pressure to afford O-methyl-D-serine benzyl ester as a light brown liquid (32.6 g, 66%). Chiral purity: 94.6%. Chemical purity: 98.3%.

(8) Into a Parr hydrogenator under a nitrogen atmosphere was charged a solution of O-methyl-D-serine benzyl ester (30 g, 0.143 mol) in methanol (210 mL). A slurry of 10% PdC (50% wet; 3.9 g, 13% w/w) in methanol (90 mL) was slowly added. The equipment was flushed with hydrogen gas, then a 50 psi pressure of hydrogen was maintained for 45 minutes. Water was added into the reaction mass to dissolve the solid material. The reaction mixture was filtered through celite and washed with methanol (150 mL) and water (30 mL). The solvent was evaporated under reduced pressure to afford crude product (16.6 g). A slurry was made from a portion (14 g) of the resulting material in acetone. The slurry was stirred for 2 hours at 25 C., then filtered. The wet filter cake was washed with acetone. The residue was dried at 50 C. for 1 hour, to afford the title compound (13 g, 90.2%). Chiral HPLC: 93.5%. Chemical HPLC: 96.8%.

EXAMPLE 5

(R)-2-Acetylamino-3-Methoxypropionic Acid (Method 1)

(9) To a suspension of O-methyl-D-serine (12 g, 0.1 mol) in tetrahydrofuran (72 mL) and water (12 mL) was added acetic anhydride (9.53 mL, 0.1 mol) over a period of 15 minutes at 20 C. The temperature was maintained at 20 C. for 4 hours. The solvent was completely evaporated from the reaction mixture at 50 C. The reaction mixture was then subjected to co-distillation with toluene (360 mL) at 60 C., to afford crude solid material (16 g). Toluene (60 mL) was added and the contents were stirred for 1 hour at 25-27 C., then filtered. The wet filter cake was washed with toluene. The residue was dried under suction for 15 minutes, then dried under vacuum at 50 C. to constant weight, to give the title compound (14.7 g, 93.4%). Chiral HPLC: 93.0%. Chemical HPLC: 97.4%.

EXAMPLE 6

N-Acetyl-O-Methyl-D,L-Serine

(10) Into a vessel, equipped with a mechanical stirrer, was added O-methyl-D,L-serine (1.0 eq.) at 20 C. Tetrahydrofuran (6 volumes) and water (0.65 volume) were added. Acetic anhydride (1.2 eq.) was added dropwise over 5 minutes. The white suspension was stirred mechanically until complete conversion was observed by HPLC monitoring (approximately 16 h), by which time the reaction mixture had become homogeneous. The tetrahydrofuran and water were removed azeotropically. Toluene was added in order to effect complete removal of water and acetic acid (KF and GC control). The wet solid was dried at 40 C. under vacuum overnight. The title compound (90% yield) was obtained as a white solid with a chemical purity of >98% as measured by HPLC.

EXAMPLE 7

(R)-2-Acetylamino-3-Methoxypropionic Acid (Method 2)

(11) In a vessel, equipped with a magnetic stirrer and pH controller, N-acetyl-O-methyl-D,L-serine (3 g) was dissolved in demineralized water (30 mL) and the pH was adjusted to 7.5-8.0 with 5N sodium hydroxide solution. Acylase I from Porcine Kidney (EC: 3.5.1.14) (50 mg) was added and the solution maintained at 25 C. under mild agitation overnight. The pH was adjusted to 2.7 with concentrated HCl and the aqueous solution injected onto Dowex 50WX4-50 ion exchange resin (50 mL) conditioned at pH 3.8. The resulting material was eluted with water at pH 2.4. The aqueous solution thereby obtained was then evaporated to dryness under vacuum to afford the title compound (1.5 g, 50%) as an off-white solid.

EXAMPLE 8

(R)-2-Acetylamino-N-benzyl-3-methoxypropionamide (Method 1)

(12) To a suspension of (R)-2-acetylamino-3-methoxypropionic acid (5 g, 31.05 mmol) in tetrahydrofuran (50 mL), under a nitrogen atmosphere at 20 C., was added isobutyl chloroformate (4.04 mL, 31.05 mmol) over a period of 10 minutes. The temperature was maintained at 20 C. for 10 minutes. 4-Methylmorpholine (3.42 mL, 31.05 mmol) was added over a period of 10 minutes, and the temperature was maintained for a further 10 minutes. Benzylamine (3.39 mL, 31.05 mmol) was added directly into the reaction mixture via a syringe at 20 C. over a period of 10 minutes. The temperature of the reaction mixture was maintained at 20 C. for a further 20 minutes. The reaction mixture was quenched with aqueous HCl (1M; 21.88 mL). Solvent was removed by evaporation at 45-50 C., and crude material (16 g) was isolated. Ethyl acetate (50 mL) was added, and the reaction mixture was washed with water (22.5 mL). The organic layer was dried over sodium sulphate and the solvent was completely removed by evaporation to give crude material (5.77 g). A portion (5.5 g) of this material was dissolved in ethyl acetate (50 mL) at 50-55 C. The temperature was maintained for 10 minutes, before cooling to 25 C. After stirring at this temperature for 2 hours the reaction mixture was filtered. The wet filter cake was washed with ethyl acetate (2.5 mL). The residue was dried under suction for 20 minutes, then dried under vacuum at 40 C. to constant weight, to give the title compound (1.38 g, 18.5%). Chiral purity: 99.2%. Chemical HPLC: 96.8%.

EXAMPLE 9

(R)-2-Acetylamino-N-benzyl-3-methoxypropionamide (Method 2)

(13) (R)-2-Acetylamino-3-methoxypropionic acid (8.06 g, 0.05 mol) was dissolved in tetrahydrofuran (80 mL). Isobutyl chloroformate (7.8 mL, 0.06 mol) was added at 10 C. within 10 minutes, followed by 4-methylmorpholine (6.6 mL, 0.06 mol), and the mixture was stirred at 10 C. for 40 minutes. A solution of benzylamine (6.55 mL, 0.06 mol) in tetrahydrofuran (10 mL) was then added at 10 C. The mixture was allowed to warm to room temperature, the solvent evaporated and the residue dissolved in dichloromethane. The solution was successively washed with water (30 mL), 1M HCl (30 mL), 5% sodium hydrogencarbonate solution (30 mL) and again with water (30 mL). The solvent was evaporated and the residue crystallized in ethyl acetate to afford the title compound (7.09 g, 57%). LCMS analysis: 98.0%.

EXAMPLE 10

(R)-2-Acetylamino-N-benzyl-3-methoxypropionamide (Method 3)

(14) O-Methyl-D-serine (1.19 g, 0.01 mol) was suspended in tetrahydrofuran (40 mL). The suspension was heated to reflux and treated dropwise with a solution of triphosgene (1.09 g) and tetrahydrofuran (30 mL). The residual cloudiness dispersed into solution. The reaction mixture was stirred overnight at room temperature, then filtered to clarity. The solvent was completely removed by rotary evaporation to afford an oil (1.06 g, 73.7%). This material was dissolved in ethyl acetate (20 mL) and treated with benzylamine (0.78 g) at room temperature. The reaction mixture was stirred for 2 hours and then washed with water (23 mL). The solvent was completely removed from the organic phase by rotary evaporation to afford an oil (1.12 g). The resulting crude material was dissolved in dichloromethane (25 mL). After the addition of acetic anhydride (0.82 g, 0.08 mol), the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was successively extracted with water (5 mL), 1M hydrochloric acid (5 mL), 5% aqueous sodium hydrogencarbonate solution (5 mL) and water (5 mL). The solvent was completely removed from the organic phase by rotary evaporation to afford the title compound (1.20 g, 88.9%) as a colourless crystalline solid. HPLC: 93.46% (R) isomer.

EXAMPLE 11

(R)-2-Acetylamino-N-benzyl-3-methoxypropionamide (Method 3)

(15) N-Acetyl-O-methyl-D,L-serine (10 g, 62.1 mmol) was placed in a glass reactor and fresh demineralised water (90 mL) was added. Freshly prepared 5M aqueous sodium hydroxide solution (approx. 11.5 mL) was added to adjust the reaction mixture to pH 8. Acylase I from Porcine Kidney (EC: 3.5.1.14; grade I) (0.1 g) was added, and the homogeneous solution was stirred mechanically at 100 r.p.m. at 25 C. for 1 h. Molar conversion of N-acetyl-O-methyl-D,L-serine (400 MHz .sup.1H NMR, D.sub.2O): 94%. Enantiomeric excess of O-methyl-L-serine (HPLC): 99%.

(16) HCl (6M; 10% v/v) was added to the reaction mixture, which was placed in Falcon centrifuge tubes. The tubes were centrifuged at 10,000 r.p.m for 10 minutes at 25 C. The precipitated enzyme was recovered. Final pH of reaction mixture: 2.5. Recovery of enzyme: 100%.

(17) To wet Dowex 50WX4-50 ion exchange resin (1 volume) was added HCl (pH 3.6) in order to obtain a slurry (orange supernatant). The slurry was transferred onto a glass chromatography column. The volume of the resin in the column, known as the Bed Volume (BV), corresponded to approximately 1.15 times the volume of wet resin. The column was eluted (approx. 4 BV) until a colourless eluate was obtained. Freshly centrifuged reaction mixture (0.375 volumes compared with wet resin) was added at a rate of 5-6 mL per minute. The column was then eluted with HCl (pH 3.6; 3.3 BV) at a rate of 5-6 mL per minute, to provide a solution of title compound. Next, the column was eluted with demineralised water (7 BV) at a rate of 6-7 mL per minute until the pH was about 6.5. Subsequently, the column was eluted with ammonia (1M; 3.3 BV), to provide a solution of O-methyl-L-serine.

(18) The solution of O-methyl-L-serine was concentrated by rotary evaporation at 40 C. under maximum vacuum, to afford C)-methyl-L-serine as a white solid. Crude yield: 94.9%. No racemisation.

(19) The solution of title compound was evaporated. To remove residual acetic acid, excess toluene (0.13 volumes compared with wet resin) was added, and the resulting solution was evaporated at 40 C. under maximum vacuum. The addition of toluene and evaporation was repeated, to afford the title compound as a light yellow solid. Crude yield: 94.7%. No racemisation.

EXAMPLE 12

(R)-2-Acetylamino-N-benzyl-3-methoxypropionamide (Method 4)

(20) The enzyme-free reaction mixture obtained from Example 11, second paragraph, was azeotroped with toluene to remove residual acetic acid. To the resulting material was added a 5M aqueous solution of sodium hydroxide to adjust to pH 9. L-Tartaric acid (0.6 equivalents) was added, and the reaction mixture was concentrated to dryness by rotary evaporation at 60 C. under maximum vacuum. Isopropanol (10 volumes) was added, and the resulting slurry was magnetically stirred for approximately 30 minutes at room temperature. The suspension was filtered under vacuum through a sintered glass. The filtrate was concentrated by rotary evaporation, to afford the title compound as a yellow oil. Crude yield: 43%. .sup.1H NMR (400 MHz, D.sub.2O): 77.5 mol % title compound and 22.5 mol % O-methyl-L-serine.