| 61% |
Stage #1: (R)-2-N-acetamido-3-methoxypropionic acid; benzylamine In tetrahydrofuran at 20℃;
Stage #2: With 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride In tetrahydrofuran at 20℃; |
|
| 57% |
Stage #1: (R)-2-N-acetamido-3-methoxypropionic acid With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at -10℃; for 0.833333h;
Stage #2: benzylamine In tetrahydrofuran at -10 - 20℃; |
9.2
(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-methylmorp holine (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 HC1 (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%. |
| 57% |
Stage #1: (R)-2-N-acetamido-3-methoxypropionic acid With isobutyl chloroformate In tetrahydrofuran at -10℃; for 0.166667h;
Stage #2: With 4-methyl-morpholine In tetrahydrofuran at -10℃; for 0.666667h;
Stage #3: benzylamine In tetrahydrofuran at -10 - 20℃; |
9 (R)-2-Acetylamino-N-benzyl-3-methoxypropionamide (Method 2)
(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%. |
| 55% |
Stage #1: (R)-2-N-acetamido-3-methoxypropionic acid With isobutyl chloroformate In tetrahydrofuran at -15℃; for 0.166667h; Green chemistry;
Stage #2: benzylamine With 4-methyl-morpholine In tetrahydrofuran at -15 - 20℃; for 4h; Green chemistry; |
3 Manufacturing of (R)-2-acetamido-N-benzyl-3-methoxypropionamide(Compound represented by the formula (1)),
(R) -2-acetamido-3-methoxypropanoic acid (compound represented by the formula (3)) (13 g, 0.081 mole)After cooling to -15 ° C or lower, isobutyl chloroformate (IBC, 11.1 ml, 0.085 mole) was added thereto and stirred for 10 minutes.4-Methylmorpholine (NMM, 9.3 ml, 0.089 mole) was added dropwise at -10 & lt;BelowAnd then benzylamine (BnNH2) was added at the same temperature.The mixture was kept at -15 ° C to -10 ° C for 1 hour, then heated to room temperature and stirred for 3 hours.The reaction solvent was removed by concentration, and then 130 ml of methylene chloride and 13 ml of purified water were added thereto. The aqueous layer was extracted again with 60 ml of methylene chloride, and the oil layers were combined.To the separated oil layer were sequentially washed 100 ml of a 2 wt% aqueous hydrochloric acid solution, 100 ml of a 2 wt% aqueous sodium hydrogencarbonate solution and 10 wt% of brine, respectively, and the oil layer was separated and the separated oil layer was concentrated under reduced pressure.Ethyl acetate (130 ml) was added to the concentrated residue, the temperature was raised to 60 ° C and dissolved, and normal heptane (130 ml) was gradually added.The reaction product was cooled to room temperature and stirred for 2 hours, and the resulting solid was filtered and dried to obtain 11 g of lacosamide (I)Yield 55%, purity 99.7% chiral purity 100% |
| 55% |
Stage #1: (R)-2-N-acetamido-3-methoxypropionic acid With isobutyl chloroformate In tetrahydrofuran at -15℃; for 0.166667h;
Stage #2: benzylamine With 4-methylmorpholine N-oxide In tetrahydrofuran at -15 - 20℃; for 4h; |
3 Preparation of lacosamide,(R)-2-acetamido-N-benzyl-3-methoxypropionamide(the compound represented by Formula 1)
(R)-2-acetamido-3-methoxypropanoic acid (the compound represented by Formula 3) (13 g, 0.08 1 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-meth- ylmorpholine (NMM, 9.3 ml, 0.089 mole) was added drop- wise while maintaining the temperature below -10° C., and benzylamine (BnNH2) 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 mE of methylenechioride and 13 ml of purified watet 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). Yield: 55%; purity 99.7%; and chiral purity: 100%10036] ‘H-NMR (DMSO) ö (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) |
|
Stage #1: (R)-2-N-acetamido-3-methoxypropionic acid With 4-methyl-morpholine; isobutyl chloroformate In ethyl acetate at -20℃; for 0.5h; Inert atmosphere;
Stage #2: benzylamine In ethyl acetate at -20 - 30℃; for 1.5h; |
4
Example 4:Preparation of lacosamide: Into a 2L, four-necked RB flask was charged 1250 ml of ethyl acetate and 25 g of N-acetyl-O-methyl-D-serine under nitrogen atmosphere. The reaction mass was cooled to -20°C and added 16.5 g of N-methylmorpholine. Isobutyl chloroformate (22.3 g) was slowly added to the reaction mass. After stirring for 30min benzylamine (17.5 g) was slowly added to the reaction mass and stirred for 30min. Temperature of the reaction mass was raised to 25-30°C and stirred for lh. Reaction mass was quenched with 100 ml of IN HC1 and transferred into a separating funnel. Organic layer was washed with brine and dried over sodium sulphate. Solvent was partially distilled of from the mass under vacuum. The residue was kept under stirring and filtered the solid. The wet solid was recrystallized from ethyl acetate to get 35g of pharma grade lacosamide. Chiral HPLC purity is >99.9% and the related impurities are <0.5%. |
|
With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at -78 - 35℃; for 0.5h; |
17
Example-17: Preparation of lacosamide compound of formula-1:; 4-methylmorpholine (1.1 ml) followed by isobutylchloroformate (1.3 ml) was added to a suspension of (R)-2-acetamido-3-methoxypropanoic acid compound of formula-11 (1.0 gram) in tetrahydrofuran (20 ml) at -78 to -75°C, benzylamine (1.35 ml) was added to it and the reaction mixture temperature was raised to 30-35°C then stirred for 30 minutes. The reaction mixture was filtered and the filtrate was distilled off under reduced pressure. Water was added to the obtained residue and washed with toluene. Aqueous layer was extracted with chloroform and this chloroform layer was distilled off completely under reduced pressure to get the title compound.Yield: 0.8 grams. |
|
Stage #1: (R)-2-N-acetamido-3-methoxypropionic acid With isobutyl chloroformate In tetrahydrofuran at -10℃; for 0.166667h;
Stage #2: With 4-methyl-morpholine In tetrahydrofuran at -10℃; for 0.666667h;
Stage #3: benzylamine In tetrahydrofuran at -10℃; for 0.333333h; |
5
Example 5- Preparation of substantially optically pure (R)-2-acetamido-N-benzyl-3- methoxypropion-amide (B1) from N-acetyl-O-methyl-D-serine (C1)To a solution of (C1) in tetrahydrofuran (10 volumes) cooled at -10 °C was added dropwise over 10 minutes 1 .0 equiv of isobutylchloroformate. After 10 minutes, 1.0 equiv of N-methylmorpholine was added dropwise over 10 minutes and the suspension stirred at -10 °C for 40 minutes. 1 Equiv of benzylamine was then added over 10 minutes and the suspension stirred for 10 minutes. The reaction was quenched at -10 °C by addition of 1 N HCI (0.6 equiv) to pH 0-1. The reaction was transferred to a separatory funnel and diluted with 20 volumes of dichloromethane. The layers were separated and the aqueous layer extracted again with 20 volumes of dichloromethane. The combined organic layers were washed with a 5% solution of sodium bicarbonate and evaporated to dryness.The crude (B1 ) was suspended in ethyl acetate (10 volumes), heated to reflux, seeded with form (I) of (R)-2-acetamido-N-benzyl-3-methoxypropion-amide and slowly cooled down to room temperature to afford substantially optically pure (R)-2-acetamido-N- benzyl-3-methoxypropion-amide (B1) in crystalline form (I).(R)-2-acetamido-N-benzyl-3-methoxypropion-amide obtained accord ing to th is example is characterized by a powder X-ray diffractogram (Figure 1) comprising peaks at 8.40, 10.52, 13.06, 15.72, 16.75, 17.8, 19.68, 21 .15, 21 .37, 24.37, 25.04 and 25.49 +/- 0.25 (°2Θ), measured with a Cu-Κα irradiation. |
| 35 g |
Stage #1: (R)-2-N-acetamido-3-methoxypropionic acid With 4-methyl-morpholine; isobutyl chloroformate In ethyl acetate at -20℃; for 0.5h; Inert atmosphere;
Stage #2: benzylamine In ethyl acetate at 25 - 30℃; for 1.5h; Inert atmosphere; |
4 Example 4 ;Preparation of lacosamide
Into a 2 L, four-necked RB flask was charged 1250 ml of ethyl acetate and 25 g of N-acetyl-O-methyl-D-serine under nitrogen atmosphere. The reaction mass was cooled to -20° C. and added 16.5 g of N-methylmorpholine. Isobutyl chloroformate (22.3 g) was slowly added to the reaction mass. After stirring for 30 min benzylamine (17.5 g) was slowly added to the reaction mass and stirred for 30 min. Temperature of the reaction mass was raised to 25-30° C. and stirred for 1 h. Reaction mass was quenched with 100 ml of 1N HCl and transferred into a separating funnel. Organic layer was washed with brine and dried over sodium sulphate. Solvent was partially distilled of from the mass under vacuum. The residue was kept under stirring and filtered the solid. The wet solid was recrystallized from ethyl acetate to get 35g of pharma grade lacosamide. Chiral HPLC purity is >99.9% and the related impurities are <0.5%. |
|
Stage #1: (R)-2-N-acetamido-3-methoxypropionic acid With isobutyl chloroformate In tetrahydrofuran at -10℃; for 0.166667h;
Stage #2: With 4-methyl-morpholine In tetrahydrofuran at -10℃; for 0.833333h;
Stage #3: benzylamine for 0.333333h; |
5 Example 5 Preparation of substantially optically pure (R)-2-acetamido-N-benzyl-3-methoxypropion-amide (B1) from N-acetyl-O-methyl-D-serine (C1)
To a solution of (C1) in tetrahydrofuran (10 volumes) cooled at -10 ° C. was added dropwise over 10 minutes 1.0 equiv of isobutylchloroformate. After 10 minutes, 1.0 equiv of N-methylmorpholine was added dropwise over 10 minutes and the suspension stirred at -10 ° C. for 40 minutes. 1 Equiv of benzylamine was then added over 10 minutes and the suspension stirred for 10 minutes. The reaction was quenched at -10 ° C. by addition of 1N HCl (0.6 equiv) to pH 0-1. The reaction was transferred to a separatory funnel and diluted with 20 volumes of dichloromethane. The layers were separated and the aqueous layer extracted again with 20 volumes of dichloromethane. The combined organic layers were washed with a 5% solution of sodium bicarbonate and evaporated to dryness. The crude (B1) was suspended in ethyl acetate (10 volumes), heated to reflux, seeded with form (I) of (R)-2-acetamido-N-benzyl-3-methoxypropion-amide and slowly cooled down to room temperature to afford substantially optically pure (R)-2-acetamido-N-benzyl-3-methoxypropion-amide (B1) in crystalline form (I). (R)-2-acetamido-N-benzyl-3-methoxypropion-amide obtained according to this example is characterized by a powder X-ray diffractogram (FIG. 1) comprising peaks at 8.40, 10.52, 13.06, 15.72, 16.75, 17.8, 19.68, 21.15, 21.37, 24.37, 25.04 and 25.49±0.25 (°2θ), measured with a Cu-Kα irradiation. |
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