Process for preparing lacosamide and related compounds

Abstract

There is provided a process for the preparation of Lacosamide in a particular polymorphic form, which process involves the isolation of a salt of formula I: according to the methods defined in the application. ##STR00001##

Claims

1. A salt of formula I, ##STR00034## or a solvate thereof.

2. The salt according to claim 1 having a percentage diastereomeric excess of greater than 90%.

3. A process for the isolation of salt of formula I, ##STR00035## which process comprises precipitation of the salt of formula I from a mixture of N-formyl-L-leucine, a compound of formula II, ##STR00036## and a solvent for the compound of formula II.

4. The process according to claim 3, wherein the N-formyl-L-leucine has a percentage enantiomeric excess of the L-enantiomer of greater than 95%.

5. The process according to claim 3, wherein the process comprises the addition of N-formyl-L-leucine to a mixture of a compound of formula II and a solvent for the compound of formula II.

6. The process according to claim 3, wherein the process is performed in the presence of a racemisation promoter.

7. The process according to claim 6, wherein the racemisation promoter is selected from 5-nitrosalicylic aldehyde, 3,5-dichlorosalicylic aldehyde, 2-nitro benzaldehyde, 4-nitrobenzaldehyde, 2,4-dinitrobenzaldehyde, salicylic aldehyde and pyridoxal-5′-phosphate.

8. The process according to claim 7, wherein the racemisation promoter is present at about 2 to about 20 mol % relative to the compound of formula II.

9. The process according to claim 3, wherein the solvent for the compound of formula II is one or more organic solvents selected from the group consisting of toluene, a xylene, ethylbenzene, an alkylbenzene, a halobenzene, a nitrobenzene, a methoxybenzene, 2-propanol, methylcyclohexane, a heptane, an alkenyl acetate and an alkyl acetate.

10. The process according to claim 9, wherein the solvent for the compound of formula II is isopropyl acetate, toluene or a mixture of isopropyl acetate and isopropanol.

11. The process according to claim 3, wherein the process is conducted at a temperature from about 30° C. to about 80° C.

12. A process for preparing a compound of formula IIA, ##STR00037## said process comprising the steps of isolating, by precipitation, a salt of formula I ##STR00038## from a mixture of N-formyl-L-leucine. a compound of formula II, and a solvent for the compound of formula II, and reacting the salt of formula I with a base.

13. A process for the preparation of Lacosamide (formula III): ##STR00039## which process comprises: isolating a salt of formula I, ##STR00040## by precipitation of the salt of formula I from a mixture of N-formyl-L-leucine, a compound of formula II, ##STR00041## and a solvent for the compound of formula II, followed by reaction of the salt of formula I with an acetyl donor optionally in the presence of a base.

14. The process according to claim 13, wherein the acetyl donor is a branched or linear C.sub.2-8 1-alkenyl acetate.

15. The process according to claim 14, wherein the acetyl donor is isopropenyl acetate.

16. The process according to claim 13, wherein the acetyl donor is acetic anhydride.

17. The process of claim 13 wherein the Lacosamide is then crystallized in a suitable solvent to yield a polymorph of Lacosamide having an X-ray powder diffraction pattern containing specific peaks of high intensity at 8.4° (±0.1°), 13.1° (±0.1°), 20.9° (±0.1°), 21.5° (±0.1°), 25.0° (±0.1°) and 25.4° (±0.1°) 2θ.

18. The process of claim 17 wherein the compound of formula II is prepared by a process which comprises the following steps: (a) reacting a compound of formula IX, ##STR00042## wherein L.sup.1 and L.sup.2 independently represent a halogen atom, to produce a compound of formula IV, ##STR00043## wherein R.sup.x represents a NH-benzyl group; and (b) reducing the compound of formula IV obtained in step (a) to produce the compound of formula II ##STR00044##

19. The process of claim 18 further comprising preparing a pharmaceutical formulation by admixing the Lacosamide with one or more pharmaceutically acceptable adjuvants, diluents and/or carders and, optionally, one or more other pharmacologically active agents.

20. A process for the preparation of Lacosamide (formula III): ##STR00045## which process comprises isolating a salt of formula I, ##STR00046## by precipitating the salt from a mixture of N-formyl-L-leucine, a compound of formula II, ##STR00047## and a solvent for the compound of formula II: reacting the salt of formula I with a base to produce a compound of formula IIA, ##STR00048## followed by reaction of the compound of formula IIA with an acetyl donor.

21. The process according to claim 20, wherein the acetyl donor is a branched or linear C.sub.2-8 1-alkenyl acetate.

22. The process according to claim 21, wherein the acetyl donor is isopropenyl acetate.

23. The process according to claim 20, wherein the acetyl donor is acetic anhydride.

24. The process of claim 20 wherein the Lacosamide is then crystallized in a suitable solvent to yield a polymorph of Lacosamide having an X-ray powder diffraction pattern containing specific peaks of high intensity at 8.4° (±0.1°), 13.1° (±0.1°), 20.9° (±0.1°), 21.5° (±0.1°), 25.0° (±0.1°) and 25.4° (±0.1°) 2θ.

Description

EXAMPLES

(1) The following examples are merely illustrative examples of the processes of the invention described herein.

(2) All equipment, reagents and solvents used were standard laboratory equipment, e.g. glassware, heating apparatus and HPLC apparatus.

Example 1

Isolation of (R)-2-amino-N-benzyl-3-methoxypropanamide without the use of a racemiser

(3) Crude racemic 2-amino-N-benzyl-3-methoxypropanamide (assay 82.5%; 5.9 g) was dissolved in isopropyl acetate (150 mL). (S)-2-Formamido-4-methylpentanoic acid (1.90 g; 0.5 eq.) was added. The suspension was heated at stirring to 82° C. A thick white slurry was formed. More isopropyl acetate (50 mL) was added. The suspension was heated to reflux in 10 minutes and then allowed to cool to 27° C. and filtered. The filter cake was washed with isopropyl acetate (10 mL). A fine white solid was obtained; dry weight 4.0 g; chiral HPLC: 93% of (R)-enantiomer, 7% of (S)-enantiomer; calculated yield of (R)-enantiomer 86%. The crude product was re-crystallized from isopropyl acetate (50 mL) n-butanol (50 mL) to obtain 3.0 g of solid (99.8% of (R)-enantiomer, 0.2% of (S)-enantiomer). Free base (R)-2-amino-N-benzyl-3-methoxypropanamide was obtained by extraction of the alkaline salt solution in water with methylene chloride and evaporation of the solvent. An almost colourless liquid, 1.59 g was obtained with 99.3% purity by HPLC area %. Chiral purity: 98.7% of (R)-enantiomer, 1.3% of (S)-enantiomer.

Example 2

Isolation of (R)-2-amino-N-benzyl-3-methoxypropanamide using a racemiser

(4) Racemic 2-amino-N-benzyl-3-methoxypropanamide (1 g; 4.56 mmol) was dissolved in isopropyl acetate (20 mL). 2-Hydroxy-5-nitrobenzaldehyde (40 mg; 5 mol %) and (S)-2-formamido-4-methylpentanoic acid (0.76 g; 1 eq. to racemic amine) were added. The mixture was stirred at 60° C. (oil-bath) in 17 h and then allowed to cool to 25° C. Thick slurry was filtered and washed on filter with 3 mL of isopropyl acetate. 1.3 g of white solid was obtained, chiral HPLC: 92% of (R)-enantiomer and 8% of (S)-enantiomer; calculated yield of (R)-enantiomer 71% from racemic amine.

Example 3

Acetylation of (R)-2-amino-N-benzyl-3-methoxypropanamide

(5) To a solution of (R)-2-amino-N-benzyl-3-methoxypropanamide (0.5 g; 2.38 mmol) in isopropyl acetate (5 mL) was added isopropenyl acetate (1.3 mL; 11.9 mmol). The solution was heated in oil-bath at 70-75° C. for 4 h and left then to cool to 23° C. overnight. The resulting solid was filtered and washed with isopropyl acetate (1 mL). 2-Acetamino-N-benzyl-3-methoxypropanamide (0.41 g; identity confirmed by GC-MS) with a purity of 97.2% (HPLC area %) was obtained, yield (from starting amine): 68.9%.

Example 4

Preparation of Formulations Containing Lacosamide

(6) Lacosamide (a compound of formula III), e.g. obtained by the procedures disclosed herein, may be formulated into a pharmaceutically acceptable formulation using standard procedures.

(7) For example, there is provided a process for preparing a pharmaceutical formulation comprising Lacosamide, or a salt thereof, which process is characterised in that it includes as a process step a process as hereinbefore defined. The skilled person will know what such pharmaceutical formulations will comprise/consist of (e.g. a mixture of active ingredient (i.e. Lacosamide or a salt thereof) and pharmaceutically acceptable excipient, adjuvant, diluent and/or carrier).

(8) There is further provided a process for the preparation of a pharmaceutical formulation comprising Lacosamide (or a salt thereof), which process comprises bringing into association Lacosamide, or a pharmaceutically acceptable salt thereof (which may be formed by a process as hereinbefore described), with (a) pharmaceutically acceptable excipient(s), adjuvant(s), diluent(s) and/or carrier(s).

(9) When a pharmaceutical formulation is referred to herein, it includes a formulation in an appropriate dosage form for intake (e.g. in a tablet form). Hence, any process mentioned herein that relates to a process for the preparation of a pharmaceutical formulation comprising Lacosamide, or a salt thereof, may further comprise an appropriate conversion to the appropriate dosage form (and/or appropriate packaging of the dosage form).

Example 5

Deracemisation of 2-amino-N-benzyl-3-methoxypropanamide in toluene

(10) 2-Amino-N-benzyl-3-methoxypropanamide in toluene (207 g; 12% racemic amine by NMR assay) was concentrated to 151.6 g (16.4% solution). 2-Hydroxy-5-nitrobenzaldehyde (1.1 g; 5 mol %) and (S)-2-formamido-4-methylpentanoic acid (20 g) were added. The mixture was stirred at 65-66° C. The enantiomer ratio after 45 h was 92:7 (R:S). The product was filtered and washed with toluene/isopropanol mixture. Crude wet product was re-slurried in 150 mL toluene/iPrOH (95/5) at 65-70° C. for 1 h to afford 36.8 g of (R)-salt with 99.1% purity by HPLC and undetectably low content of (S)-enantiomer. Yield of (R)-salt 84%.

Example 6

Deracemisation of 2-amino-N-benzyl-3-methoxypropanamide in a mixture of toluene and 2-propanol

(11) 2-Amino-N-benzyl-3-methoxypropanamide (10 g; 43.7 mmol) in toluene/iPrOH (88.4 g; 97/3 w/w) was mixed with (S)-2-formamido-4-methylpentanoic acid (7.02 g) and 2-hydroxy-5-nitrobenzaldehyde (0.37 g; 5 mol %). The mixture was heated in an oil-bath at 64-65° C. The enantiomer ratio was 92:7 (R:S) after 51 h. The suspension was cooled and filtered. The wet crude product (18.72 g) was re-slurried in 60 mL toluene/i-PrOH mixture (97/3 w/w) at 60-65° C. for 1 h to afford 13.85 g of (R-salt) with 98.4% purity by HPLC. Chiral purity 99.6% of (R)-enantiomer and 0.4% of (S)-enantiomer. Yield of (R)-salt 86%.

Example 7

Acetylation of the Salt of Formula I with Isopropenyl Acetate in Isopropyl Acetate

(12) The N-formyl-L-leucine salt of (R)-2-amino-N-benzyl-3-methoxypropanamide (3 g) was suspended in iPrOAc (60 mL) and isopropenyl acetate (3.5 mL; 32.1 mmol) was added. Conversion was over 99% at 85° C. in 2 h by HPLC analysis. The mixture was cooled and NaOH aqueous solution was added. The layers were separated. The organic phase was concentrated. The precipitate was filtered and washed with iPrOAc. After drying 0.8 g of white solid with 95.2% HPLC purity was achieved. From filtrate crop 2 (0.37 g) was isolated with 91.6% HPLC purity. Overall yield 55.3%.

Example 8

Acetylation of the N-formyl-L-leucine salt of (R)-2-amino-N-benzyl-3-methoxypropanamide with acetic anhydride in water

(13) The N-formyl-L-leucine salt of (R)-2-amino-N-benzyl-3-methoxypropanamide (3.0 g) was suspended in water (20 mL). The mixture was stirred at 22° C. for 40 min. Acetic anhydride (1.3 mL) was added portion-wise in 6 h at 22-25° C. The product was filtered, washed with isopropyl acetate and dried in air. White crystals (1.58 g) were obtained containing 12.4% N-formyl-L-leucine and 86.1% Lacosamide by HPLC area %.

Example 9

Acetylation of the N-formyl-L-leucine salt of (R)-2-amino-N-benzyl-3-methoxypropanamide with acetic anhydride in a mixture of water and dichloromethane

(14) The N-formyl-L-leucine salt of (R)-2-amino-N-benzyl-3-methoxypropanamide (6.0 g) was suspended in water (15 mL) and dichloromethane (25 mL). Acetic anhydride (3.4 g; 2 eq) was added at stirring in 30 min at 21 to 25° C. Stirring was continued for 1 h at 21-24° C. The mixture was neutralized with concentrated NaOH solution. The phases were separated. The water phase was extracted with dichloromethane (5 mL). The combined organic solution was washed with concentrated solution of sodium hydrogen carbonate (5 mL). The organic solution was concentrated in vacuum. Ethyl acetate (30 mL) was added to the residue and mixture was heated to reflux. The solution was stirred and cooled to 10° C. The product was filtered, washed with cold ethyl acetate and dried. Lacosamide (2.52 g) as white solid was obtained with 99.3% purity by HPLC. Yield 64%.

Example 10

Acetylation of the N-formyl-L-leucine salt of (R)-2-amino-N-benzyl-3-methoxypropanamide with acetic anhydride in a mixture of water and tert-amyl alcohol

(15) The N-formyl-L-leucine salt of (R)-2-amino-N-benzyl-3-methoxypropanamide (2.0 g) was suspended in water (5 mL) and t-amyl alcohol (10 mL). Acetic anhydride (1.1 g) was added in 20 min at 22 to 25° C. Stirring was continued for 1 h at 23-24° C. The mixture was neutralized with concentrated NaOH solution and phases were separated. The organic phase was washed with sodium hydrogen carbonate solution (4 mL). The combined water phase was extracted with t-amyl alcohol (5 mL). The organic solution was concentrated in vacuum. The solid residue (2.27 g) was heated with isopropyl acetate (15 mL) to reflux, filtered and allowed to cool to room temperature. The precipitate was filtered off, washed with isopropyl acetate and dried. Lacosamide (0.95 g) as white solid was obtained with 98.9% Lacosamide purity by HPLC area %. Yield 73%.

Example 11

Preparation of (R,S)-methyl 2-chloro-3-methoxypropionate

(16) ##STR00024##

(17) NaOMe (30% in MeOH, 120.3 g; 0.669 mol) was diluted with MeOH (120 g; 154 mL) to reach 15% w/w concentration of NaOMe in MeOH. The resulting solution was cooled to 0±5° C. and then methyl-2,3-dichloropropionate (100.1 g; 0.637 mol) was added at 5° C. The reaction mixture was stirred at 0±5° C. for 2 h, after which the excess NaOMe was neutralized by alcoholic HCl solution (4.6 mL, 20% in i.PrOH) until pH 5-6 was reached. The precipitate was filtered off and the cake washed with cold MeOH (100 mL). Excess MeOH was removed by distillation at atmospheric pressure. The product was purified by distillation in vacuo to obtain methyl 2-chloro-3-methoxypropionate (81.8 g, 0.533 mol, >99 GC area %, yield 83.6%).

Example 12

Preparation of (R,S)-methyl 2-bromo-3-methoxypropionate

(18) ##STR00025##

(19) Methyl acrylate (151.8 g; 1.76 mol) was dissolved in MTBE (400 ml). Bromine (308.4 g; 1.92 mol; 100 mL) was added dropwise to the resulting solution at 18-25° C. The mixture was allowed to stir for 18 h at room temperature. Excess bromine was quenched with ca. 30% sodium sulfite solution (100 mL). The brownish organic phase became colourless after vigorous stirring. The layers were separated and the organic phase was concentrated in vacuo. The crude methyl 2,3-dibromopropionate (524.7 g; 91% pure by GC area %) was then added dropwise at 18-20° C. into a sodium methoxide solution prepared from sodium methoxide (317.5 g; 1.76 mol) and methanol (634.0 g; 810 mL). The resulting mixture was allowed to stir for 15 min at room temperature. GC analysis revealed: Br-acrylate 1.5%; methyl 2-bromo-3-methoxypropionate 96% by area %. Methanol was removed by distillation in vacuo. Toluene (200 mL) was added and the mixture was concentrated again. The resulting precipitate was filtered off and the filtrate was distilled in vacuo. A product fraction was collected at 32 mbar and 92-93° C., affording methyl 2-bromo-3-methoxypropionate (251.8 g, 1.28 mol, 96 GC area %, yield 70% based on methyl acrylate).

Example 13

Preparation of (R,S)—N-Benzyl-2-benzylamino-3-methoxypropionamide

(20) ##STR00026##

(21) Methyl 2-chloro-3-methoxypropionate (3.70 kg, 24.2 mol) was added to benzylamine (13.50 kg, 126 mol) over 30 min. The mixture was stirred at 120±5° C. for 6 h, while the resulting MeOH was collected as a distillate. After cooling the reaction mixture below 100° C., water (4.35 kg) and NaOH (89% by titration, 1.22 kg, 27.27 mol, 1.13 eq.) were added and the resulting two phase system was thoroughly mixed and allowed to settle before the phases were separated. Aqueous NaCl (ca. 20%, 2.65 kg) was added to the organic phase, the mixture was allowed to settle and the layers were separated to remove excess NaOH. The process was repeated until pH 10-11 was obtained. The organic phase was dried by distillation at 100-150 mbar and 56-87° C. which produced a small amount of solid precipitated. The residue was filtered off, the cake was washed with benzylamine (100 mL) and the filtrate subjected to further distillation to remove benzylamine (6.99 kg). The residue from the distillation was collected (7.00 kg, 22.03 mol, assay 93.7% by NMR, yield 89.9%).

Example 14

Preparation of (R,S)—N-Benzyl-2-benzylamino-3-methoxypropionamide

(22) ##STR00027##

(23) NaOMe (25% in MeOH, 46 g; 0.213 mol) was diluted with MeOH (100 g; 128 mL). The resulting solution was cooled to 0±5° C. and then methyl 2,3-dichloropropionate (32 g; 0.204 mol) was added at 5° C. The reaction mixture was stirred at 0±5° C. for 2 h after which, the excess NaOMe was neutralized by alcoholic HCl solution until pH 6-7 was reached. Benzylamine (88 g; 0.82 mol) was added to the mother liquor, and the mixture was heated to 125±5° C. while methanol was removed via distillation. After 12 h the mixture was cooled and isopropyl acetate (180 mL) and water (100 mL) were added. The aqueous phase was separated and removed, and the organic phase was washed with aqueous acetic acid (16%, 60 mL) and then with water (3×50 mL). The solvent was partially distilled off to remove water to obtain about 58 g of an oil, containing 48.6 g of (R,S)—N-benzyl-2-benzylamino-3-methoxypropionamide (0.163 mol, yield 80%) which was used in the next step without any isolation or further purification.

Example 15

Preparation of (R,S)—N-Benzyl-2-amino-3-methoxypropionamide [(R,S)-II]

(24) ##STR00028##

(25) N-Benzyl-2-benzylamino-3-methoxypropanamide (400 g, 94%, 1.26 mol), toluene (400 g) and a catalyst (5% Pd/C, 50% moist, 21.5 g, 0.4 mol %) were sequentially introduced into a pressure reactor. The atmosphere in the reactor was exchanged to N.sub.2 and then to H.sub.2. The reaction mixture was stirred at 100° C. and 2.0 to 2.5 bar for 4 h and then cooled to 22° C., after which the catalyst was filtered off and the cake washed with toluene (60 mL). The toluene solutions were combined to give a toluene solution of (R,S)—N-benzyl-2-amino-3-methoxypropionamide (798.7 g, HPLC purity 94.7%, yield 94.5%).

Example 16a

Preparation of (R,S)—N-Benzyl-2-amino-3-methoxypropionamide

(26) ##STR00029##

(27) An oil (58 g; prepared according to Example 14) containing 48.6 g of (R,S)—N-benzyl-2-benzylamino-3-methoxypropionamide (0.163 mol) was placed in a pressure reactor and diluted with isopropyl acetate (600 mL). A catalyst (5% Pd/C, 50% moist, 2.9 g, 5% w/w) was added to this solution and the atmosphere in the reactor was exchanged to N.sub.2 and then to H.sub.2. The reaction mixture was stirred at 85° C. and 2.0 bar for about 12 h and then cooled to 22° C., after which the catalyst was filtered off and the cake washed with isopropyl acetate (50 mL) to give (R,S)—N-benzyl-2-amino-3-methoxypropionamide as an isopropyl acetate solution (36 g, HPLC purity 90%, corresponding to 32.4 g of (R,S)—N-benzyl-2-amino-3-methoxypropionamide (0.156 mol), yield 95%, in 650 mL of isopropyl acetate).

Example 16b

Preparation of (R,S)—N-Benzyl-2-amino-3-methoxypropionamide

(28) The procedure of Example 16a was reproduced using 300 mL of isopropyl acetate in the initial stage. The final product was an isopropyl acetate solution of (R,S)—N-benzyl-2-amino-3-methoxypropionamide which was obtained in a similar yield with a similar purity (as determined by HPLC).

Example 17

Preparation of (R)—N-benzyl-2-amino-3-methoxypropanamide N-formyl-L-leucine salt

(29) ##STR00030##

(30) An isopropyl acetate solution of (R,S)—N-Benzyl-2-amino-3-methoxypropionamide (36 g, 90% pure in 650 mL of solvent; prepared according to Example 16a), was added to N-formyl-L-leucine (24.8 g, 0.156 mol), 5-nitro-salicylic aldehyde (1.25 g, 7.4 mmol), and isopropanol (35 mL), and the mixture was stirred at 65° C. for about 16 h. The mixture was then cooled at room temperature and filtered. The cake was washed with isopropyl acetate/isopropanol (90/10, 2×20 mL) to give (R)—N-benzyl-2-amino-3-methoxypropanamide N-formyl-L-leucine salt (48 g, 0.131 mol, HPLC purity >99%, d.e. ≧99%, yield 84%).

Example 18a

Preparation of (R,S)—N-benzyl-2-amino-3-methoxypropanamide from the corresponding (S) enantiomer

(31) ##STR00031##

(32) A solution containing toluene (90 mL) and enriched (S)—N-benzyl-2-amino-3-methoxypropanamide (13 g, 62 mmol, e.e. 80%) was treated with 5-nitro-salicylic aldehyde (0.5 g, 3.0 mmol) and heated at 65° C. for 16 h to afford (R,S)—N-benzyl-2-amino-3-methoxypropanamide quantitatively.

Example 18b

Preparation of (R,S)—N-benzyl-2-amino-3-methoxypropanamide from the corresponding (S) enantiomer

(33) A solution containing toluene (90 mL) and enriched (S)—N-benzyl-2-amino-3-methoxypropanamide (13 g, 62 mmol, e.e. 80%) was treated with a mixture containing salicylic aldehyde (0.5 g, 4.0 mmol), potassium carbonate (0.2 g, 1.4 mmol), and tetrabutylammonium bromide (0.1 g, 0.3 mmol), and heated at 65° C. for 16 h to afford (R,S)—N-benzyl-2-amino-3-methoxypropanamide (e.e. for (S)-enantiomer: 10%).

Example 19

(R)—N-benzyl-2-acetamido-3-methoxypropanamide (Lacosamide)

(34) ##STR00032##

(35) Acetic anhydride (12 g, 0.117 mol) was added to a mixture of (R)—N-benzyl-2-amino-3-methoxypropanamide N-formyl-L-leucine salt (40 g, 0.109 mol, d.e. ≧99%), isopropyl acetate (180 mL), water (25 mL) and anhydrous sodium acetate (9.5 g, 0.116 mol) at room temperature. After about 2 h, the mixture was treated with sodium hydroxide (30%) to reach pH 6-7 and heated to obtain two clear phases. The aqueous phase was separated and extracted with isopropyl acetate (3×15 mL). The organic phases were brought together and washed with an aqueous solution of potassium bicarbonate (20%, 15 mL). The organic phase was then distilled off in a Dean-Stark equipment to reduce the water content of the organic phase (to K.F. <0.5). After the product was slowly cooled to 0 to 5° C., the product was filtered, washed with cold isopropyl acetate (2×15 mL) and dried to obtain (R)—N-benzyl-2-acetamido-3-methoxypropanamide (23.2 g, 92.6 mmol, HPLC purity >99%, d.e. ≧99%, yield 85%).

Example 20

Recovery of N-Formyl-L-Leucine

(36) The aqueous phase obtained during the process of Example 19 was treated with 32% aqueous HCl to reach pH 2-3. The resulting slurry was stirred for about 1 h at 20-25° C., then filtered and washed with water (3×20 mL) to obtain N-formyl-L-leucine as a white solid (13.8 g, yield 80%). This product may be used as such for a new preparation of (R)—N-benzyl-2-amino-3-methoxypropanamide N-formyl-L-leucine salt, for example according to the procedure of Example 17.

Example 21

Crystallization of Lacosamide

(37) ##STR00033##

(38) Lacosamide (20 g; obtained according to Example 19) were placed in a round bottom flask equipped with mechanical stirrer. Wet isopropyl acetate (180 mL) was added (Karl Fisher value of the solvent was 1.3-1.5%). The mixture was heated at reflux (complete solution at 70° C.). The solution was filtered while hot on paper and the filter was washed with hot wet isopropyl acetate (10 mL). The solution was distilled off in a Dean-Stark apparatus to remove water (the final KF of the solution was <0.1%; the temperature of reflux raised from 82 to 86° C.). The resulting solution was cooled until a solid formed (at approximately 60 to 65° C.) and heated again up to 70 to 75° C. without total dissolution occurring. The resulting suspension was maintained at this temperature for 1 hour. The suspension was then cooled to room temperature over 2 hours and finally to 0 to 5° C. over one hour. The suspension was maintained at 0 to 5° C. for another hour. The solid was obtained by filtration at this temperature and the filter was rinsed with 20 mL of cold anhydrous isopropyl acetate. 24.7 g of wet product was obtained (corresponding to 18.4 g of dry product after drying at 65° C. under vacuum).

(39) The solid form of Lacosamide obtained here was characterized by X-ray Powder Diffraction (XRDP) using a Philips PW1800/10 diffractometer, equipped with software X′Pert High Score—v. 2.0a (PANalytical) and radiation Cu Kα. The peak intensities recorded are shown in Table 1.

(40) TABLE-US-00001 TABLE 1 XRPD data for Lacosamide d-spacing Rel. Int. Pos. [° 2θ] [Å] [%] 6.5369 13.52180 1.86 8.3517 10.58717 55.99 10.4373 8.47587 7.84 13.0610 6.77854 98.21 15.6497 5.66262 17.05 16.6567 5.32246 22.31 17.7101 5.00820 8.83 19.6494 4.51807 24.04 20.8974 4.25098 59.96 21.4595 4.14089 51.50 22.6569 3.92469 4.05 24.0023 3.70765 23.49 24.2687 3.66756 30.93 24.9861 3.56385 100.00 25.4293 3.50274 48.18 26.1188 3.41181 15.02 27.0174 3.30035 11.09 28.0044 3.18622 10.23 28.4115 3.14149 9.93 31.5304 2.83750 9.57 32.1197 2.78677 8.28 33.6009 2.66724 13.54 34.0918 2.62995 4.63 36.4979 2.46191 6.13 37.4792 2.39968 4.97 38.5423 2.33589 9.37 38.9474 2.31253 7.16 40.4187 2.23168 9.78 41.1488 2.19376 8.72 43.9879 2.05853 4.30 45.0527 2.01232 3.97 45.9179 1.97640 5.87 47.0455 1.93163 7.38 47.7339 1.90536 5.13 51.2066 1.78401 2.68 53.8756 1.70176 1.02 57.3169 1.60750 1.22 61.8188 1.49956 0.79

(41) FT-IR spectra were recorded using a Jasco FT/IR 460 plus spectrometer. The spectra were recorded using the diffuse reflection method and the sample was prepared mixing about 5 mg of product with 500 mg of KBr (10% w/w).

(42) Absorptions were observed at ca.: 3300, 3100, 2880, 1630, 1550, 1140, 970, 690, 600 and 500 cm.sup.−1.

(43) DSC data was collected using a Mettler-Toledo DSC 822e instrument. Standard DSC experiment: heat 30-250° C. at 10°/min.

(44) A single transition was observed with the following results: Onset 145.52° C. Peak 146.54° C. Endset 149.13° C.

ABBREVIATIONS

(45) DCM dichloromethane d.e. diastereomeric excess DMAA N,N-dimethylacetamide DMAP dimethylaminopyridine DMF dimethylformamide DSC Differential scanning calorimetry e.e. enantiomeric excess GC gas chromatography h hours HPLC high performance liquid chromatography iPrOAcisopropyl acetate iPrOH isopropyl alcohol IR Infrared KF Karl Fischer MeOH methanol MTBE methyl-tert-butyl ether NMP N-methylpyrrolidone NMR Nuclear magnetic resonance RA racemic 2-amino-N-benzyl-3-methoxypropionamide RT room temperature TEA triethylamine THF tetrahydrofuran TMEDA tetramethylethylenediamine XRPD X-ray powder diffraction