1,1-Dimethylethyl N-[(1R)-1-(methoxymethyl)-2-oxo-2-[(phenylmethyl)amino]ethyl]carbamate

Put toluene at room temperature (4.8L) with Lacosamide stage II product (1kg), cooled to 0 °C, put sodium hydroxide solution 1 (0.54kg), tetrabutylammonium bromide (0.186 kg) with dimethyl sulfate (0.86 kg), heated to 30 °C, stir for 90 minutes. Extracted with toluene, put 5percent sodium bicarbonate solution, separate the organic phase. Put cyclohexane, stirred for 10 minutes and concentrated at 50 °C under reduced pressure for 2 hours. Drying to obtain lacosamide stage III. Yield of about 96.28percent.2.2. (R)-boc-2-amino-N-benzyl-3-methoxy-propionamide (IV)In a 4 L flask with overhead stirrer, thermometer, dropping funnel and under nitrogen were combined 120 g (R)-boc-2-amino-N-benzyl-3-hydroxy-propionamide (III) (0.407 mol) and 1 kg dichloromethane. The reaction was cooled on ice to 4-8° C. and 6.9 g tetrabutylammonium bisulfate (6.8 mmol) and 285 g of 20percent sodium hydroxide in water (0.475 mol) added. To the reaction was then added 154 g (1.22 mol) dimethyl sulfate and the reaction stirred at 4-8° C. for 4 hours and overnight at 20-25° C. A sample showed greater than 98percent methylation of the starting (R)-boc-2-amino-N-benzyl-3-hydroxy-propionamide. The reaction was quenched by additing 330 g of 25percent ammonium hydroxide solution in water plus a further 330 g water and stirred for 2 hours. The phases were then separated and the aqueous phase extracted with 340 g dichloromethane. The combined dichloromethane phases were washed with 450 ml water, then the dichloromethane was exchanged for tert-butyl methyl ether (MTBE) and the product crystallised from 345 ml MTBE at 4° C. overnight. The crystals were filtered and washed 2 times with 45 ml MTBE and dried to yield 95.3 g (75.8percent yield), HPLC purity=98.6percent, ee >99percent, Toluene (820 mL), Intermediate III (50 g), methyl p-toluenesulfonate (63.5 g), Tetrabutylammonium bromide (5.4 g) was added and the mixture was cooled with stirring to -1 to 2 ° C. Potassium hydroxide aqueous solution (40 g / 34 mL) was added at -1 to 2 ° C, and the addition was completed in about 5 minutes. The addition was complete, continue to control the temperature at -1 ~ 2 reaction 4 ~ 4.5 hours (TLC detection or HPLC control) to stop the reaction. After completion of the reaction, water (400 mL) was added to separate the layers. Organic layer followed by 5percent phosphoric acid, saturated sodium bicarbonate, water each200mL wash. Decompression 40 ~ 45 ° C The solvent was evaporated to give an oil, the reaction was used directly for the next step. HPLC purity 95percent, chiral Purity 99.1percent.Toluene (330 mL) was added sequentially to the 1 L reaction flask, The compound of formula II (20.00 g, 68 mmol)P-toluenesulfonic acid methyl ester (63.50 g, 340 mmol), Tetrabutylammonium bromide (2.63 g, 8.16 mmol), Stir evenly, An aqueous solution of potassium hydroxide (16.00 g of potassium hydroxide + 16 mL of water) was added at room temperature, Plus complete, room temperature reaction 3 hours.Reaction completed, adding water (160mL), stirring 5min, standing stratification, liquid separation, Organic layer followed by 5percent phosphoric acid(80 mL), water (160 mL x 2), and the organic layer was concentrated at 55 ° C under reduced pressure. The solvent was evaporated to give 60.97 g of an oil.The product of this example was the same as in by isolation and identification.To a 1L reaction flask were sequentially added toluene (330 mL), Compound II (20.00 g, 68 mmol), methyl p-toluenesulfonate (38.10 g, 204 mmol), tetrabutylammonium bromide (2.63 g, 8.16 mmol), Stir well, add aqueous sodium hydroxide solution (16.00g of sodium hydroxide + 16mL of water) at room temperature, complete the addition, and react at room temperature for 3 hours. After the reaction is complete, add water (160 mL), stir for 5 min, stand for layering, separate the liquid, and use 5percent phosphoric acid in order for the organic layer.(80 mL) and water (160 mL×2) were washed. The organic layer was concentrated under reduced pressure at 55° C., and the solvent was evaporated to give 38.5 g of an oil.Toluene (330 mL) was added sequentially to a 1L reaction flask, Compound II (20.00 g, 68 mmol), Methyl p-toluenesulfonate (38.10 g, 204 mmol), Tetrabutylammonium bromide (2.63 g, 8.16 mmol), Stir well, An aqueous solution of sodium hydroxide (16.00 g of sodium hydroxide + 16 mL of water) was added at room temperature.After the addition, the reaction was carried out at room temperature for 3 hours.After the reaction is complete, add water (160 mL) and stir for 5 min.Static stratification, liquid separation, The organic layer was successively washed with 5percent phosphoric acid (80 mL) and water (160 mL×2), and the organic layer was concentrated under reduced pressure at 55° C.After the solvent was distilled off, 38.5 g of an oil was obtained.To a solution of acid (R)-9 (0.7 g, 3.2 mmol) in dry THF was added N-methylmorpholine (0.43 mL, 3.8 mmol) at -78 °C under an argon atmosphere. After 5 min, isobutyl chloroformate (0.5 mL, 3.8 mmol) was added and stirred for another 5 min. To this reaction mixture benzylamine (0.4 mL, 3.8 mmol) was added at -78 °C after which the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was filtered, and washed with ethylacetate. The solvent was removed under reduced pressure and the crude product was subjected to column chromatography (silica gel, petroleum ether/acetone, 85:15) to yield (R)-10 as a colorless solid (0.9 g, 90percent); mp 63-64 °C; (c 0.9, CHClExample-5 To a solution of acid 5 (0.985 g, 4.49 mmol) in dry THF (10ml) was added N-methylmorpholine (0.6 mL, 5.39 mmol) at -78 °C under an argon atmosphere.After 5 min, isobutyl chloroformate (0.7 mL, 5.39 mmol)was added and stirred for another 5 min. To this reaction mixture benzyl amine (0.6 mL, 5.39 mmol) was added at -78 °C andthe reaction mixture was allowed to come up to room temperature and stirred foranother 1 h. After completion of the reaction (TLC), the reaction mixture wasfiltered through a pad of celite, and washed with ethyl acetate (20 mL). Thesolvent was removed under reduced pressure and the crude reaction mixture wassubjected to flash chromatography (CombiFlash RSynthesis of (R)-N-Benzyl-2-Boc-amino-3-methoxypropionamide[0157] (R)-2-N-Boc-amino-3-methoxypropanoic acid (15.0 g, 68.4 mmol), phenylmethanamine (7.33 g, 68.4 mmol), and DMAP (4.17 g, 34.2 mmol) were dissolved in DCM (150 mL). The solution was cooled in an ice-bath and EDC (21 .21 g, 137 mmol) was added dropwise to the solution. Once addition was complete, the reaction mixture stirred at warmed to room temperature and stirred for two hours. Then DCM (200 ml) was added to the mixture. The DCM organic phase was washed with HThe above prepared compound of formula III (30.3g, 0 . 100mol) in the dichloromethane solution 0-5°C, added benzylamine (10.7g, 0 . 100mol) methylen chloride (22 ml) solution. In 0-5 °C reaction 30 minutes with water (88 ml), 10percent sodium hydroxide solution (88 ml), 0.6mol/L hydrochloric acid (88 ml), water (88 ml) washing the reactant, is distilled under reduced pressure to dry obtains the type compound IV 30.8g (yield 100percent, HPLC purity 93.0percent, chiral purity 95.8percent).A mixture of 2, 4-dioxo-3-azaspiro[5.5]undecan-3-yl N-(tert-butoxycarbonyl)-O-methyl-d-serinate Ib (Scheme 5) (3.0g, 7.53mmol) and benzyl amine (0.97g, 9.05mmol) was vigorously stirred for 3h at ambient temperature. After completion of the reaction, methyl tert-butyl ether (20mL) was added and stirred at room temperature for 1h. The reaction mixture was filtered, and washed with methyl tert-butyl ether (5mL). The filtrate was washed with 5percent aq HCl solution (10mL), water (2×10mL), brine (10mL), dried over NaA solution of tert-butyl [(2R)-l-(benzylamino)-3-methoxy-l-oxopropan-2-yl]carbamate (1.019 mol) obtained in Example 3 in methanol (300 ml) was heated at 50 °C with and Methanolic HCl (300 ml, 10percent) was added under stirring. The reaction mixture was stirred at 50 °C for 2 h, evaporated under reduced pressure. Methanol (300 ml) was added to the residue and evaporated under reduced pressure to provide HCl salt of O- methyl-N-benzyl-D-serinamide in oil form having HPLC purity more than 90percent. (0146) The above HCl salt of O-Methyl-N-benzyl-D-Serinamide (1.019 mol) was dissolved in methylene dichloride at room temperature and sodium acetate (125.4 g, 1.529 mol) was added under stirring. Acetic anhydride (127.05 g, 1.223 mol) was added slowly and stirred for 2-3 h. The reaction mass was washed with water (1200 ml) and the layers were separated. The organic layer was evaporated under reduced pressure and the residue was subjected to precipitation by dissolving in Ethyl acetate (2700 ml) and adding n-Heptane (3300 ml). The precipitated solid was filtered under reduced pressure to obtain crude Lacosamide having HPLC purity more than 98percent..Toluene (820 mL), Intermediate III (50 g), methyl p-toluenesulfonate (63.5 g), Tetrabutylammonium bromide (5.4 g) was added and the mixture was cooled with stirring to -1 to 2 ° C. Potassium hydroxide aqueous solution (40 g / 34 mL) was added at -1 to 2 ° C, and the addition was completed in about 5 minutes. The addition was complete, continue to control the temperature at -1 ~ 2 reaction 4 ~ 4.5 hours (TLC detection or HPLC control) to stop the reaction. After completion of the reaction, water (400 mL) was added to separate the layers. Organic layer followed by 5percent phosphoric acid, saturated sodium bicarbonate, water each200mL wash. Decompression 40 ~ 45 ° C The solvent was evaporated to give an oil, the reaction was used directly for the next step. HPLC purity 95percent, chiral Purity 99.1percent.Toluene (330 mL) was added sequentially to the 1 L reaction flask, The compound of formula II (20.00 g, 68 mmol)P-toluenesulfonic acid methyl ester (63.50 g, 340 mmol), Tetrabutylammonium bromide (2.63 g, 8.16 mmol), Stir evenly, An aqueous solution of potassium hydroxide (16.00 g of potassium hydroxide + 16 mL of water) was added at room temperature, Plus complete, room temperature reaction 3 hours.Reaction completed, adding water (160mL), stirring 5min, standing stratification, liquid separation, Organic layer followed by 5percent phosphoric acid(80 mL), water (160 mL x 2), and the organic layer was concentrated at 55 ° C under reduced pressure. The solvent was evaporated to give 60.97 g of an oil.The product of this example was the same as in by isolation and identification.To a 1L reaction flask were sequentially added toluene (330 mL), Compound II (20.00 g, 68 mmol), methyl p-toluenesulfonate (38.10 g, 204 mmol), tetrabutylammonium bromide (2.63 g, 8.16 mmol), Stir well, add aqueous sodium hydroxide solution (16.00g of sodium hydroxide + 16mL of water) at room temperature, complete the addition, and react at room temperature for 3 hours. After the reaction is complete, add water (160 mL), stir for 5 min, stand for layering, separate the liquid, and use 5percent phosphoric acid in order for the organic layer.(80 mL) and water (160 mL×2) were washed. The organic layer was concentrated under reduced pressure at 55° C., and the solvent was evaporated to give 38.5 g of an oil.Toluene (330 mL) was added sequentially to a 1L reaction flask, Compound II (20.00 g, 68 mmol), Methyl p-toluenesulfonate (38.10 g, 204 mmol), Tetrabutylammonium bromide (2.63 g, 8.16 mmol), Stir well, An aqueous solution of sodium hydroxide (16.00 g of sodium hydroxide + 16 mL of water) was added at room temperature.After the addition, the reaction was carried out at room temperature for 3 hours.After the reaction is complete, add water (160 mL) and stir for 5 min.Static stratification, liquid separation, The organic layer was successively washed with 5percent phosphoric acid (80 mL) and water (160 mL×2), and the organic layer was concentrated under reduced pressure at 55° C.After the solvent was distilled off, 38.5 g of an oil was obtained.The above prepared compound of formula III (30.3g, 0 . 100mol) in the dichloromethane solution 0-5°C, added benzylamine (10.7g, 0 . 100mol) methylen chloride (22 ml) solution. In 0-5 °C reaction 30 minutes with water (88 ml), 10percent sodium hydroxide solution (88 ml), 0.6mol/L hydrochloric acid (88 ml), water (88 ml) washing the reactant, is distilled under reduced pressure to dry obtains the type compound IV 30.8g (yield 100percent, HPLC purity 93.0percent, chiral purity 95.8percent).A mixture of 2, 4-dioxo-3-azaspiro[5.5]undecan-3-yl N-(tert-butoxycarbonyl)-O-methyl-d-serinate Ib (Scheme 5) (3.0g, 7.53mmol) and benzyl amine (0.97g, 9.05mmol) was vigorously stirred for 3h at ambient temperature. After completion of the reaction, methyl tert-butyl ether (20mL) was added and stirred at room temperature for 1h. The reaction mixture was filtered, and washed with methyl tert-butyl ether (5mL). The filtrate was washed with 5percent aq HCl solution (10mL), water (2×10mL), brine (10mL), dried over Na2SO4, and evaporated under reduced pressure. The crude product solidified while standing overnight at room temperature to yield tert-butyl (R)-(1-(benzylamino)-3-methoxy-1-oxopropan-2-yl) carbamate Ic as a colorless solid (2.1g, 90.4percent); mp 62'64°C (lit.23 63'64°C); [alpha]D25=?20.8 (c 0.9, CHCl3) [lit.23 '20.5]; 97.68percent purity by HPLC (Method-d, Table 1); eepercent: 99.44percent (Method-j, Table 1) [(R)-isomer Rt=7.65min; (S)-isomer Rt=8.51min]. IR (KBr, cm'1): vmax 3326, 3030, 2971, 2950, 2927, 2852, 2824, 1684, 1650, 1528, 1496, 1453, 1393, 1364, 1351, 1317, 1284, 1252, 1227, 1171, 1115, 1095, 1046, 1021, 919, 870, 750, 697, 652; 1H NMR (300MHz, CDCl3): deltaH 1.43 (s, 9H), 3.36 (s, 3H), 3.47'3.52 (dd, J=9.3, 6.3Hz, 1H), 3.82'3.86 (dd, J=9.3, 3.9Hz, 1H), 4.27 (br, 1H), 4.48 (br s, 2H), 5.41 (br, 1H), 6.74 (br, 1H), 7.24'7.35 (m, 5H); 13C NMR (75MHz, CDCl3): deltaC 169.3, 154.5, 137.0, 127.5, 126.4, 79.2, 71.1, 58.0, 53.0, 42.3, 27.2; MS: m/z 331 [M+Na]+.A mixture of (R)-tert-butyl-4-(methoxymethyl)-5-oxazolidinone (7.0 g), benzyl amine (6.5 g) and triethylamine (5.1 1 g) in methyl tert-butyl ether (15 mL) was stirred at 60- 65°C for 10- 12h. After completion of the reaction, methyl tert-butyl ether was added to reaction mixture and acidified with 20percent aqueous potassium hydrogen sulphate solution (~ 30 mL) at 10~15°C. The organic layer was washed with water (2x 15 mL) and concentrated under reduced pressure to get the title compound. Weight: 9.0 g Yield: 96.45percent

Molecular Weight:308.37
XLogP3:1.7
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:8
Exact Mass:308.17360725
Monoisotopic Mass:308.17360725
Topological Polar Surface Area:76.7
Heavy Atom Count:22
Complexity:360
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes