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Product Details of [ 196601-69-1 ]

CAS No. :196601-69-1 MDL No. :MFCD14708219
Formula : C11H16N2O2 Boiling Point : -
Linear Structure Formula :- InChI Key :WPLANNRKFDHEKD-SNVBAGLBSA-N
M.W : 208.26 Pubchem ID :10104501
Synonyms :

Safety of [ 196601-69-1 ]

Signal Word:Warning Class:
Precautionary Statements:P261-P280-P301+P312-P302+P352-P305+P351+P338 UN#:
Hazard Statements:H302-H315-H319-H335 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 196601-69-1 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 196601-69-1 ]

[ 196601-69-1 ] Synthesis Path-Downstream   1~49

  • 1
  • [ 108-24-7 ]
  • [ 196601-69-1 ]
  • lacosamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
90% With pyridine; dmap In tetrahydrofuran for 1h; Ambient temperature;
88% With pyridine In tetrahydrofuran at 20℃; for 1h; enantioselective reaction;
81.8% at 10 - 25℃; 3 Example 3 (Synthesis of R-2-acetamido-N-benzyl-3-methoxypropionamide) The methoxypropionamide methylene chloride solution of Example 2 was mixed with 42 g of acetic anhydride solution into the methoxypropionamide methylene chloride solution temperature control unit,Acetic anhydride solution temperature control unit, temperature control 10 ~ 25 , and then into the reaction unit 2 reaction 10-20 minutes, the micro-reactor for the next step.The reaction solution was added to 150 ml of water, and the dichloromethane phase was dried over anhydrous sodium sulfate, and the mixture was extracted with dichloromethane Distillation of 1/2 to give a Racamide solution. Cooling to 0-5 crystallization 0.5h, filter, 30ml dichloromethane leaching filter cake. 50-60 blast drying products 97.38g. Purity 99.97%, chiral purity 99.96%, yield 81.8%.
80% With dmap In dichloromethane at 20℃; for 1h;
78.72% With potassium carbonate In dichloromethane 6 Add dichloromethane and water to 50g intermediate M5,Adjust the pH to 8-9 with potassium carbonate solution, add acetic anhydride dropwise to the temperature, after the reaction is complete, separate extraction,Concentrate the dichloromethane layer to obtain 28 g of crude lacosamide; add ethyl acetate to the crude lacosamide after refluxing to dissolve, add activated carbon for decolorization, and filter while hot.After cooling and crystallization, 20.82g of lacosamide is obtained. The yield is 78.72% and the isomer is less than 0.01%.
74.16% With triethylamine In cyclohexane; ethyl acetate at 25 - 40℃; 8 Example - 8: Preparation of (2R)-2-acetamido-N-benzyl-3-methoxypropanamide (Lacoasmide).To a solution of (2/?)-2-Amino-N-benzyl-3-methoxypropanamide (60.0 gms) and triethylamine (7.29 gms) in cyclohexane (600 ml) charged ethyl acetate (540 ml) and added acetic anhydride (35.29gms) slowly maintaining the temperature at 25 - 30°C in 15 - 20 minutes. Raised the temperature of the reaction mass to 35 - 40°C and maintained for 4 hours. After completion of the reaction the reaction mass was cooled to 0 to 5°C within lhour and maintained for 1.5 hours. Filtered the reaction mass at 0 - 5°C and washed with cooled 1 : 1 mixture of ethyl acetate: cyclohexane (2 x 120 ml). The wet solid was taken in diethyl ether (612ml) and stirred for 6 hours at 20 - 25°C. Filtered the product (2R)-2- acetamido-N-benzyl-3-methoxypropanamide and washed with diethyl ether and dried at 50 - 55°C till constant weight.Yield= 53.48 gms,O/o Yield= 74.16%.
69.8% In dichloromethane at 0 - 20℃; for 1h; 3.4 The (R)-2-amino-N-b8nzyl-3-methoxypropionamide solution prepared above5 was cooled to <5°C and acetic anhydride (10ml, 0.106mol) added at <15°C.The reaction mixture is warmed to room temperature over 30 minutes and aged for a further 30 minutes. The mixture is then washed with water (44ml),8% sodium bicarbonate (44ml) and water (44ml). The methylene chloride was exchanged for ethyl acetate by distillation and the solution distilled to a volume o of 115ml. The product was crystallised by cooling the solution to 0-5O and the pure Lacosamide isolated by filtration (18.7g, 69.8%) HPLC purity 99.98%,Chiral purity 99.8% ee.
66.4% In dichloromethane; water at 10 - 20℃; for 0.5h; 6 Example 5: Prepration of lacosamide In 10-20 °C to the above prepared compound of formula V (20.8g, 0 . 100mol) water/methylene chloride mixed solution by adding acetic anhydride (12.3g, 0 . 120mol) of dichloromethane (62 ml) solution, and in 10-20 °C reaction 30 minutes, after the reaction, using 30% potassium carbonate alkalise to pH= 8-9 extraction after the layered. Dichloromethane is used for further water (92 ml) extraction, and water (62 ml) washing the combined organic layer, is distilled under reduced pressure to dry to obtain lacosamide (16.6g, 66.4%), HPLC purity 99.8%, chiral purity 99.9% ee.
In ethyl acetate at 5 - 30℃; for 1.33333 - 1.41667h; 7.b; 8.b Example 7b N-benzyl-O-methyl-D-serinamide (50 g), prepared by sequentially following Example-1 to Example 4, was mixed with ethyl acetate (500 ml) at ambient temperature and stirred to get clear solution. To this solution, dimethylaminopyridine (1.04 g) was added at ambient temperature. The solution was cooled to 10° to 5°C and then acetic anhydride (24.48 g) was slowly added to it for 10-15 minutes at 10° to 5°C. The solution was stirred for 10 minutes at 10° to 5°C and raised to room temperature (25°-30°C) in over 30 minutes. The solution was further stirred for 30 minutes room temperature. The reaction mixture was washed with 8% sodium bicarbonate (250 ml) solution. It was again washed with water (250 ml). The layers were separated and solvent was completely recovered under vacuum at 40-48°C to get a solid product. Yield = 49.5 gm; mp: 142-143°C. Chiral purity of lacosamide by HPLC, 99.98%.; Example 8b: (Preparation of Lacosamide); N-benzyl-O-methyl-D-serinamide (50 g), prepared by sequentially following Example 1, 5, 6 and 4, was mixed with ethyl acetate (500 ml) at ambient temperature and stirred to get clear solution. To this solution, dimethylaminopyridine (1.04 g) was added at ambient temperature. The solution was cooled to 10° to 5°C and then acetic anhydride (24.48 g) was slowly added to it for 10-15 minutes at 10° to 5°C. The solution was stirred for 10 minutes at 10° to 5°C and raised to room temperature (25°-30°C) in over 30 minutes. The solution was further stirred for 30 minutes at room temperature. The reaction mixture was washed with 8% sodium bicarbonate (250 ml) solution. It was again washed with water (250 ml). The layers were separated and solvent was completely recovered under vacuum at 40-48°C to get solid product. Yield = 49.5 gm; mp: 142-143°C. Chiral purity of lacosamide by HPLC, 99.98%.
In dichloromethane at 5 - 30℃; for 1.33333 - 2.33333h; 7.a; 8.a; 9; 10 N-benzyl-O-methyl-D-serinamide (50 g), prepared by sequentially following Example 1 to Example 4, was mixed with dichloromethane (500 ml) at ambient temperature and stirred to get clear solution. To this solution, dimethylaminopyridine (1.04 g) was added at ambient temperature. The solution was cooled to 10° to 5°C and then acetic anhydride (24.48 g) was slowly added to it for 10-15 minutes at 10° to 5°C. The solution was stirred for 10 minutes at 10° to 5°C and raised to room temperature (25°-30°C) in over 30 minutes. The solution was further stirred for 30 minutes at room temperature. The reaction mixture was washed with 8% sodium bicarbonate (250 ml) solution. It was again washed with water (250 ml). The layers were separated and solvent was completely recovered under vacuum at 40-48°C to get a solid product. Yield = 50 gm; mp: 142-143°C. Chiral purity of lacosamide by HPLC, 99.98%.; Example 8a: (Preparation of Lacosamide); N-benzyl-O-methyl-D-serinamide (50 g), prepared by sequentially following Example 1, 5, 6 and 4, was mixed with dichloromethane (500 ml) at ambient temperature and stirred to get clear solution. To this solution, dimethylaminopyridine (1.04 g) was added at ambient temperature. The solution was cooled to 10° to 5°C and then acetic anhydride (24.48 g) was slowly added to it for 10-15 minutes at 10° to 5°C. The solution was stirred for 10 minutes at 10° to 5°C and raised to room temperature (25°-30°C) in over 30 minutes. The solution was further stirred for 30 minutes at room temperature. The reaction mixture was washed with 8% sodium bicarbonate (250 ml) solution. It was again washed with water (250 ml). The layers were separated and solvent was completely recovered under vacuum at 40-48°C to get solid product. Yield = 49 gm; mp: 142-143°C. Chiral purity of lacosamide by HPLC, 99.98%.; Example 9: Preparation of Lacosamide; N-benzyl-O-methyl-D-serinamide (92 g), was mixed with dichloromethane (368 ml) at ambient temperature and stirred for 10 minutes to get a clear solution. To this solution, dimethylaminopyridine (0.47 g) was added at ambient temperature. Acetic anhydride (45.09 g) was slowly added over 15-20 minutes at ambient temperature. The solution was stirred for 2 hours at room temperature. The reaction mixture was washed with sodium hydroxide (19.16 gm dissolved in 291 ml water), and deionized water (276 ml). The layers were separated and solvent was completely recovered under vacuum at 35-40 °C to get crude product. Yield = 82.6 gm; Chiral purity = 100 %. 5 gm of the crude product was dissolved in toluene (35 ml) and heated to 80 C. It was then cooled to room temperature and stirred for 30 minutes. The material was cooled further to 0 C and stirred for 30 minutes at the same temperature. The mixture was filtered, and washed with chilled toluene (2 x 10ml). The filtrate was suck-dried for 15 minutes and dried under vacuum at 45-50 C. Dried wt = 4.5 gm; Chiral purity of lacosamide by HPLC, 100.00%.; Example 10: Preparation of Lacosamide; N-benzyl-O-methyl-D-serinamide (5 g), was mixed with DCM (25 ml) at ambient temperature and stirred for 10 minutes to get a clear solution. To this solution, dimethylaminopyridine (0.025 g) was added at ambient temperature. Acetic anhydride (2.695 g) was slowly added over 10-12 minutes at ambient temperature. The solution was stirred for 30 minutes at room temperature. The reaction mixture was washed with 5% sodium bicarbonate (15 ml) solution, deionized water (15 ml), and brine (10 ml). The layers were separated and solvent was completely recovered under vacuum at 35-40 °C to get crude product. Yield = 5.9 gm. 1 gm of the crude product was dissolved in ethyl acetate (6ml) and heated to reflux to get a clear solution. The mixture was cooled to room temperature in 1 hour, cooled further to 5 C in 15 minutes, then stirred for 1 hour at 5- 10 C. The solid was filtered, and washed with chilled ethyl acetate (3.0 ml). The material was suck-dried for 15 minutes, and finally dried under vacuum at 50-55 C. Dried wt = 0.5 g. Chiral purity of lacosamide by HPLC, 100.00%.
With dmap In dichloromethane at 5 - 30℃; for 0.833333 - 0.916667h; 7.a; 8a; 9; 10 Preparation of Lacosamide Example 7a Preparation of Lacosamide N-benzyl-O-methyl-D-serinamide (50 g), prepared by sequentially following Example 1 to Example 4, was mixed with dichloromethane (500 ml) at ambient temperature and stirred to get clear solution. To this solution, dimethylaminopyridine (1.04 g) was added at ambient temperature. The solution was cooled to 10° to 5° C. and then acetic anhydride (24.48 g) was slowly added to it for 10-15 minutes at 10° to 5° C. The solution was stirred for 10 minutes at 10° to 5° C. and raised to room temperature (25°-30° C.) in over 30 minutes. The solution was further stirred for 30 minutes at room temperature. The reaction mixture was washed with 8% sodium bicarbonate (250 ml) solution. It was again washed with water (250 ml). The layers were separated and solvent was completely recovered under vacuum at 40-48° C. to get a solid product. Yield=50 gm; mp: 142-143° C. Chiral purity of lacosamide by HPLC, 99.98%. Example 8a Preparation of Lacosamide N-benzyl-O-methyl-D-serinamide (50 g), prepared by sequentially following Example 1, 5, 6 and 4, was mixed with dichloromethane (500 ml) at ambient temperature and stirred to get clear solution. To this solution, dimethylaminopyridine (1.04 g) was added at ambient temperature. The solution was cooled to 10° to 5° C. and then acetic anhydride (24.48 g) was slowly added to it for 10-15 minutes at 10° to 5° C. The solution was stirred for 10 minutes at 10° to 5° C. and raised to room temperature (25°-30° C.) in over 30 minutes. The solution was further stirred for 30 minutes at room temperature. The reaction mixture was washed with 8% sodium bicarbonate (250 ml) solution. It was again washed with water (250 ml). The layers were separated and solvent was completely recovered under vacuum at 40-48° C. to get solid product. Yield=49 gm; mp: 142-143° C. Chiral purity of lacosamide by HPLC, 99.98%. Example 9 Preparation of Lacosamide N-benzyl-O-methyl-D-serinamide (92 g), was mixed with dichloromethane (368 ml) at ambient temperature and stirred for 10 minutes to get a clear solution. To this solution, dimethylaminopyridine (0.47 g) was added at ambient temperature. Acetic anhydride (45.09 g) was slowly added over 15-20 minutes at ambient temperature. The solution was stirred for 2 hours at room temperature. The reaction mixture was washed with sodium hydroxide (19.16 gm dissolved in 291 ml water), and deionized water (276 ml). The layers were separated and solvent was completely recovered under vacuum at 35-40° C. to get crude product. Yield=82.6 gm; Chiral purity=100%. 5 gm of the crude product was dissolved in toluene (35 ml) and heated to 80° C. It was then cooled to room temperature and stirred for 30 minutes. The material was cooled further to 0° C. and stirred for 30 minutes at the same temperature. The mixture was filtered, and washed with chilled toluene (2*10 ml). The filtrate was suck-dried for 15 minutes and dried under vacuum at 45-50° C. Dried wt=4.5 gm; Chiral purity of lacosamide by HPLC, 100.00%. Example 10 Preparation of Lacosamide N-benzyl-O-methyl-D-serinamide (5 g), was mixed with DCM (25 ml) at ambient temperature and stirred for 10 minutes to get a clear solution. To this solution, dimethylaminopyridine (0.025 g) was added at ambient temperature. Acetic anhydride (2.695 g) was slowly added over 10-12 minutes at ambient temperature. The solution was stirred for 30 minutes at room temperature. The reaction mixture was washed with 5% sodium bicarbonate (15 ml) solution, deionized water (15 ml), and brine (10 ml). The layers were separated and solvent was completely recovered under vacuum at 35-40° C. to get crude product. Yield=5.9 gm. 1 gm of the crude product was dissolved in ethyl acetate (6 ml) and heated to reflux to get a clear solution. The mixture was cooled to room temperature in 1 hour, cooled further to 5° C. in 15 minutes, then stirred for 1 hour at 5-10° C. The solid was filtered, and washed with chilled ethyl acetate (3.0 ml). The material was suck-dried for 15 minutes, and finally dried under vacuum at 50-55° C. Dried wt=0.5 g. Chiral purity of lacosamide by HPLC, 100.00%.
With dmap In ethyl acetate at 5 - 30℃; for 0.833333 - 0.916667h; 7.b; 8b Preparation of Lacosamide Example 7b Preparation of Lacosamide N-benzyl-O-methyl-D-serinamide (50 g), prepared by sequentially following Example-1 to Example 4, was mixed with ethyl acetate (500 ml) at ambient temperature and stirred to get clear solution. To this solution, dimethylaminopyridine (1.04 g) was added at ambient temperature. The solution was cooled to 10° to 5° C. and then acetic anhydride (24.48 g) was slowly added to it for 10-15 minutes at 10° to 5° C. The solution was stirred for 10 minutes at 10° to 5° C. and raised to room temperature (25°-30° C.) in over 30 minutes. The solution was further stirred for 30 minutes room temperature. The reaction mixture was washed with 8% sodium bicarbonate (250 ml) solution. It was again washed with water (250 ml). The layers were separated and solvent was completely recovered under vacuum at 40-48° C. to get a solid product. Yield=49.5 gm; mp: 142-143° C. Chiral purity of lacosamide by HPLC, 99.98%. Example 8b Preparation of Lacosamide N-benzyl-O-methyl-D-serinamide (50 g), prepared by sequentially following Example 1, 5, 6 and 4, was mixed with ethyl acetate (500 ml) at ambient temperature and stirred to get clear solution. To this solution, dimethylaminopyridine (1.04 g) was added at ambient temperature. The solution was cooled to 10° to 5° C. and then acetic anhydride (24.48 g) was slowly added to it for 10-15 minutes at 10° to 5° C. The solution was stirred for 10 minutes at 10° to 5° C. and raised to room temperature (25°-30° C.) in over 30 minutes. The solution was further stirred for 30 minutes at room temperature. The reaction mixture was washed with 8% sodium bicarbonate (250 ml) solution. It was again washed with water (250 ml). The layers were separated and solvent was completely recovered under vacuum at 40-48° C. to get solid product. Yield=49.5 gm; mp: 142-143° C. Chiral purity of lacosamide by HPLC, 99.98%.
> 99.8 % ee With triethylamine In ethyl acetate at 20℃; 3.a (R)-N-benzyl-2-(benzyloxycarbonylamino)-3-methoxypropionamide (167 g, 458 mmol), (prepared as in example 1), was dissolved in ethyl acetate (1700 ml). To this solution was added Pd/C 10% (17 g). The resulting mixture was hydrogenated for 1 hour at 5-6 bar pressure at 30-35° C. The reaction mixture was then filtered to remove the catalyst. To the filtrate was added triethylamine (89.5 ml, 642 mmol) and acetic anhydride (51.9 ml, 550 mmol) in a dropwise manner. The resulting reaction mixture was stirred at room temperature for 1 hour. The product (R)-2-acetamido-N-benzyl-3-methoxypropionamide was isolated from ethyl acetate/n-heptane (1:1) mixture at 0-5° C. (98.7 g, 394.3 mmol, 86% Yields, HPLC purity 99.2 area %; ee>99.8%).
Stage #1: acetic anhydride; (R)-2-amino-N-benzyl-3-methoxypropanamide In dichloromethane at -2 - 20℃; for 3h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water 7 Crude Lacosamide Preparation of (2R)-2-(acetylamino)-3-methoxy-N-phenylmethyl)propanamideTo a cold solution (-2° C.) of 1.94 g of Intermediate 6, in 40 mL of dichloromethane was added dropwise 2.12 g of acetic anhydride maintaining the temperature below 5° C. The reaction mixture was stirred at room temperature for 3 hours and the organic phase was washed with water (2×20 mL), sodium bicarbonate solution (2×20 mL), brine and dried over sodium sulfate. The solvent was removed under vacuum and a white solid was obtained. The product was dissolved in 20 mL of ethyl acetate at reflux temperature and cooled slowly to 0° C. The solid was collected by filtration and dried yielding 1.6 g of lacosamide as a white solid.
Stage #1: acetic anhydride; (R)-2-amino-N-benzyl-3-methoxypropanamide With dmap In dichloromethane at 25 - 30℃; for 2h; Industry scale; Stage #2: With sodium hydroxide In dichloromethane; water at 25 - 30℃; Industry scale; 5 Step 5: Preparation of LacosamideTo the above organic layer, dimethyl amino pyridine (DMAP; 0.12 Kg) was added followed by addition of acetic anhydride (4.90 Kg) at 25°C to 30°C. The reaction mass was stirred for 2 hours at the same temperature. The reaction mass was washed with de-ionized water (20 L) and the pH of the organic layer was adjusted to 6.5 to 7.5 using sodium hydroxide solution (2.31 Kg in 10 L de-ionized water) at 25°C to 30°C. The organic layer was separated and activated carbon (0.49 Kg) was added to it. It was stirred for 15 minutes and then filtered through a hyflo bed. The bed was washed with dichloromethane (10 L) at 25°C to 30°C. The solvent was recovered to obtain solid. Ethyl acetate (10 L) was added to the solid at 25°C to 30°C. The solvent was again recovered at atmospheric pressure and at 40°C. The solid left was cooled to ambient temperature and ethyl acetate (84 L) was added to it. It was heated to reflux and the clear solution was obtained. It was further stirred for 5 minutes at reflux temperature. The solution obtained was passed through an 0.45 micron filter and the filter was washed with hot ethyl acetate (18 L). The solution obtained was heated to 70°C to 75°C and stirred for 5 minutes further at reflux temperature. The solution was then cooled to 30°C in 1 hour. It was further cooled to 25°C in 30 minutes. Toluene (30 L) was added to it and the resultant solution was stirred for 30 minutes at 25°C to 30°C. The solution was cooled to 0°C and stirred for 30 minutes at 0°C to 5°C. The crystals formed were filtered and washed with toluene (20 L) at 5°C to 10°C. The wet solid (crystals) were dried under vacuum at 60°C to 65°C. The dried crystals were characterized as polymorphic Form B of lacosamide.Dried weight: 5.80 KgYield: 38.68%
Stage #1: acetic anhydride; (R)-2-amino-N-benzyl-3-methoxypropanamide With dmap In water at 20 - 30℃; for 2h; Stage #2: With sodium hydroxide In water at 25 - 30℃; 1.2.2D Step 2D: Preparation of lacosamide; To the aqueous solution obtained as above, dimethyl amino pyridine (DMAP; 0.34 g) was added at ambient temperature. Acetic anhydride (14.68 g) was slowly added to the solution at 25°C to 30°C. It was stirred for 2 hours at the same temperature and then 10% sodium hydroxide (120 ml) was added into it to adjust pH 6.5-7.5 at 25-30°C.Dichloromethane (325 ml) was added to it and the reaction mass was allowed to settle for 15 minutes. The layers were separately collected. To the aqueous layer, dichloromethane (260 ml) was added, stirred and allowed to settle for 15 minutes. The layers were separated. The organic layers were combined and washed with de-ionized water (65 ml). It was stirred for 10 minutes and allowed to settle for 15 minutes. The layers were separately collected. To the organic layer, activated carbon (1.5 g) was added at ambient temperature, stirred and then filtered through a hyflo bed at 25 °C to 30°C. The hyflo bed was washed with dichloromethane (30 ml) at 25°C to 30°C. Solvent was recovered from the filtered and washed organic layer at atmospheric pressure and at 35°C to 40°C. Traces of solvent, if any, were recovered under vacuum at 35°C to 40°C to get a solid. Ethyl acetate (30 ml) was added to the solid at 25°C to 30°C. It was heated to 45°C to 50°C and stirred for 15 minutes. Solvent was recovered at atmospheric pressure and at 45°C to 50°C. Ethyl acetate (210 ml) was again added at ambient temperature. It was stirred for 60 minutes at ambient temperature. The product obtained was filtered and suck dried for 60 minutes. Ethyl acetate (540 ml) was added to the wet product obtained and heated to reflux to obtain clear solution. The solution was stirred for 5 minutes at refluxtemperature and then cooled to 30°C in 1 hour. It was again stirred for 30 minutes at 25 °C to 30°C and then cooled to 0°C to 5°C. Toluene (90 ml) was added to it at the same temperature and stirred for 30 minutes. The solid obtained was filtered and washed with toluene (60 ml) at ambient temperature. The wet solid obtained was dried under vacuum at 60°C to 65°C.Dried weight: 17.5 g (loss on drying was 0.1%)Impurity content of Formula II: Not detectable by HPLCImpurity content of Formula III: 0.01% by HPLC Impurity content of Formula II and/or Formula III in lacosamide were measured by HPLC (Agilent 1100 series) having photodiode array detectors. The analysis was performed at wavelength of 210 nm.
In dichloromethane at 20 - 25℃; for 1h; 34 Example-34: Preparation of lacosamide compound of formula-1:; Acetic anhydride (48.5 g) was added to methylene chloride layer containing (R)- N-benzyl-2-amino-3-methoxypropionamide (390 ml) obtained in example-33 at 20-25°C and stirred for an hour. The reaction mixture was washed with sodium carbonate solution followed by water, and the solvent from the reaction mixture was distilled off under atmospheric pressure. Ethyl acetate (50 ml) was added to the residue and distilled off it completely. Ethyl acetate (250 ml) was added to the obtained residue and heated to 75 - 80°C, stirred for 30 minutes and filtered through hyflow. The filtrate was cooled to 55 60°C and stirred for 4 hours. The reaction mixture was further cooled to 0-5° and stirred for 1 hr. The solid obtained was filtered off and washed with ethyl acetate. Ethyl acetate was added to the wet solid and heated to 75-80°C and stirred for 45 min at 75-80°C. The reaction mixture was cooled to 20-25 °C and stirred for 1.30 hrs. The solid obtained was filtered off, and washed with ethyl acetate and dried to get the title compound.Yield: 65 gramsPurity by HPLC: 99.86%; O-actyl impurity: 0.05%; acetamide impurity: 0.05%; amino impurity: Not detected; hydroxyl impurity: 0.01%
With pyridine In water at 5 - 30℃; 2.4 Step 4:Preparation of (R)-N-Benzyl-2-acetamido-3-methoxypropionamide (Lacosamide).; (R)-N-Benzyl-2-amino-3-methoxypropionamide (35 g, 0.1681 mol) was dissolved in DM water (400 ml) at ambient temperature. The solution was cooled to 5-10°C, followed by pyridine ( 1.76 g, 0.0222 mol) and acetic anhydride (21.5 g, 0.2106 mol) were added at 5-10°C in 15-20 min. The solution was stirred for 30-40 min at 5- 10°C and raised to room temperature (25-30°C) in over 30 min. The solution was further stirred for 30-40 min at room temperature (25-30°C). The compound was extracted with methylene chloride (2 x 200 ml). The combined organic layer was washed with hydrochloric acid (IN HC1, 70ml), followed by aqueous sodium bicarbonate solution (8% w/v, 70ml) and DM water (70ml) and distilled off MDC under vacuum at 35-40°C to get solid product. The solid was suspended in isopropyl acetate (200 ml) and stirred the suspension for 60-70 min at room temperature (25-30°C). Filtered the product and washed with isopropyl acetate. Yield: 30 g, Chiral purity: 99.5%.
With sodium hydroxide In dichloromethane; water at 4 - 20℃; for 1h; 3 3. Lacosamide ((R)-2-acetamido-N-benzyl-3-methoxypropionamide (I)) In a 1 L flask with overhead stirrer, condenser, thermometer and dropping funnel were combined 40 g (0.13 mol) (R)-boc-2-amino-N-benzyl-3-methoxy-propionamide (IV) and 400 ml dichloromethane. To this was carefully added 51.3g (0.52 mol) 37% w/w hydrochloric acid in water. The reaction was stirred at 25 °C for 3 hours, at which time a sample showed >99% hydrolysis of the boc protecting group. To the reaction was added 112 g water. The solution was then cooled on ice to 4-6 °C. With good mixing 75 g (0.62 mol) 33% w/w sodium hydroxide solution in water was then slowly added maintaining the temperature between 4-8 °C. At completion of addition, 17.3 g (0.17 mol) acetic acid anhydride was slowly added. The reaction was allowed to come to room temperature and stirred for a further 1 hour. The phases were separated and the aqueous phase extracted with 100 ml dichloromethane. The dichloromethane phases were combined and washed with 25 ml water. The dichloromethane was then exchanged for toluene and lacosamide crystallised from a mixture of 460 ml toluene plus 10 ml methanol by warming until all solids were in solution and then slowly cooling to 4-8 °C. The lacosamide was filtered and washed 2 times with 50 ml toluene. Yield 24.8 g (76.4%), purity by HPLC 99.9%, ee >99.9%, 1H NMR conforms. ee is enantiomeric excess and is calculated by determining the percentage of each separate enantiomer of a given chiral compound, such that the sum of the (R) and (S) enantiomers is 100%, and subtracting one from the other.
In dichloromethane at 20℃; for 1h; 3 3. Lacosamide ((R)-2-acetamido-N-benzyl-3-methoxypropionamide (I))In a 1 L flask with overhead stirrer, condenser, thermometer and dropping funnel were combined 40 g (0.13 mol) (R)-boc-2-amino-N-benzyl-3-methoxy-propionamide (IV) and 400 ml dichloromethane. To this was carefully added 51.3 g (0.52 mol) 37% w/w hydrochloric acid in water. The reaction was stirred at 25° C. for 3 hours, at which time a sample showed >99% hydrolysis of the boc protecting group. To the reaction was added 112 g water. The solution was then cooled on ice to 4-6° C. With good mixing 75 g (0.62 mol) 33% w/w sodium hydroxide solution in water was then slowly added maintaining the temperature between 4-8° C. At completion of addition, 17.3 g (0.17 mol) acetic acid anhydride was slowly added. The reaction was allowed to come to room temperature and stirred for a further 1 hour. The phases were separated and the aqueous phase extracted with 100 ml dichloromethane. The dichloromethane phases were combined and washed with 25 ml water. The dichloromethane was then exchanged for toluene and lacosamide crystallised from a mixture of 460 ml toluene plus 10 ml methanol by warming until all solids were in solution and then slowly cooling to 4-8° C. The lacosamide was filtered and washed 2 times with 50 ml toluene. Yield 24.8 g (76.4%), purity by HPLC 99.9%, ee >99.9%, 1H NMR conforms.
With potassium carbonate In dichloromethane at 0 - 20℃; for 1h; 5; d To the above solution of (/?)-2-Amino-iV-benzyl-3-methoxypropionamide was added potassium carbonate 164.0 g (1.18 mole) and acetic anhydride 237 g (2.32 mole) at 0- 5°C. The reaction mixture was then stirred at ambient temperature for 1 hour and washed with water. The organic layer was concentrated, the residue stripped once with ethyl acetate and then crystallized from ethyl acetate to obtain lacosamide with HPLC purity >99%, chiral purity using chiral HPLC was 99%.Repeat crystallization from ethyl acetate provides lacosamide with chiral purity > 99.5%
With dmap; tetrabutylammomium bromide In dichloromethane at 0 - 20℃; 8 Preparation of (R)-2-acetamido-N-benzyl-3-methoxypropionamide (Lacosamide)(R)-2- Amino-N-benzyl-3 -methoxypropionamide (62 gm) as obtained example 7 was dissolved in methylene chloride (620 ml) and stirred for 10 minutes. To the solution was added dimethylaminopyridine (1 gm) and tetra-butyl ammonium bromide (1 gm) at room temperature. The contents were cooled to 0 to 5°C and then added acetic anhydride (34 ml) for 15 minutes. The temperature of the reaction mass was raised to room temperature and then added water (120 ml). The separated organic layer was dried with sodium sulfate and then concentrated to obtain a residual mass. To the residual mass was added ethyl acetate and maintained for 30 minutes. The reaction mass was then cooled to 0 to 5°C and maintained for 2 hours, filtered. The solid obtained was dried to give 48 gm of lacosamide.
In dichloromethane at 27℃; for 0.5h; 4 Step-4 Preparation of (2R)-2-(acetylamino)-N-benzyl-3-methoxypropanamide (crystalline Form I) To the organic layer (dichloromethane layer) obtained as above, acetic anhydride (57.55 g) was added at 27±3°C and stirred for 30 min. at 27±3°C. DM water (290 ml) was added 27±3°C and stirred for 5-10 min. at same temperature. The layers were separated. The organic layer was collected. The organic layer was washed with 5% w/v sodium bicarbonate solution (14.5 g in 290 ml DM water), stirred at 27±3°C and allowed to settle. The organic layer was collected. The organic layer was washed with DM water, stirred at 27±3°C and allowed to settle. The organic layer was collected. Activated carbon was added 27±3°C and stirred for 30 min. at 27±3°C. Filtered the reaction mass through hyflow bed and washed the bed with dichloromethane (145 ml). Filtrate was collected. Distilled out dichloromethane at below 50°C atmospherically, Isopropyl alcohol was added at 47±3°C and stirred for 5-10 min. Distilled out Isopropyl alcohol under vacuum at 47±3°C. Isopropyl alcohol (290 ml) was added at 47±3°C and the reaction was heated at 81±3°C followed by addition of n-heptane (1450 ml) at same temperature. Stir the reaction mass for 15-20 min. at the same temperature. Cooled the reaction mass to 40±3°C and stirred for 8 hr. at the same temperature. Cooled the reaction mass to 3±3°C and stirred for 30 min. at the same temperature. Solid was filtered at 3±3°C and washed with n-heptane (145 ml) at 27±3°C. The solid was dried in vaccum at 42±3°C for 6-8 hr.
With potassium carbonate at 0 - 20℃; for 1h; 5 Example 5
Lacosamide To the above solution of (R)-2-Amino-N-benzyl-3-methoxypropionamide was added potassium carbonate 164.0 g (1.18 mole) and acetic anhydride 237 g (2.32 mole) at 0-5° C. The reaction mixture was then stirred at ambient temperature for 1 hour and washed with water. The organic layer was concentrated, the residue stripped once with ethyl acetate and then crystallized from ethyl acetate to obtain lacosamide with HPLC purity>99%, chiral purity using chiral HPLC was 99%. Repeat crystallization from ethyl acetate provides lacosamide with chiral purity>99.5%.
30 g With pyridine In water at 5 - 30℃; 2.4 Preparation of (R)-N-Benzyl-2-acetamido-3-methoxypropionamide (Lacosamide) Step 4 Preparation of (R)-N-Benzyl-2-acetamido-3-methoxypropionamide (Lacosamide) (R)-N-Benzyl-2-amino-3-methoxypropionamide (35 g, 0.1681 mol) was dissolved in DM water (400 ml) at ambient temperature. The solution was cooled to 5-10° C., followed by pyridine (1.76 g, 0.0222 mol) and acetic anhydride (21.5 g, 0.2106 mol) were added at 5-10° C. in 15-20 min. The solution was stirred for 30-40 min at 5-10° C. and raised to room temperature (25-30° C.) in over 30 min. The solution was further stirred for 30-40 min at room temperature (25-30° C.). The compound was extracted with methylene chloride (2*200 ml). The combined organic layer was washed with hydrochloric acid (1N HCl, 70 ml), followed by aqueous sodium bicarbonate solution (8% w/v, 70 ml) and DM water (70 ml) and distilled off MDC under vacuum at 35-40° C. to get solid product. The solid was suspended in isopropyl acetate (200 ml) and stirred the suspension for 60-70 min at room temperature (25-30° C.). Filtered the product and washed with isopropyl acetate. Yield: 30 g, Chiral purity: 99.5%.
49.35 g In dichloromethane at 10 - 30℃; 11 Example 11: Preparation of Lacosamide: To a solution of (R)~tert-butyl-(l -(benzylainino)-3-methoxy-l-oxopropan-2-yl) carbamate ( 06.0 g) in DCM (600 mL) was added cone. HC1 (189.38 mL) at 0-5°C and stirred for 4- 5h. The reaction mixture was decomposed with water (250 mL) at 0-5°C. The aqueous layer was washed with DCM (150 mL). To the aqueous layer was added with DCM (400 mL) and acidified with 20% aq. sodium hydroxide (-375 mL) to pH -9.0-10.0 with solution. Aqueous layer was extracted the with DCM (3x200 mL) and DCM layer was washed with water (100 mL). To the DCM" layer was added acetic anhydride (38.86g) at 30- 5°C and stirred at 25-30°C for 4-6 h. The reaction mixture was quenched with 2N HC1 (300 mL) at 25-30°C arid stirred for 20-30 min. The organic layer was washed with 20% aq. sodium bicarbonate solution (300 mL) then with DM Water (300 mL). The DCM layer was charcoalized, filtered over hyflo bed arid washed the hyflo bed with DCM (300 mL). The combined filtrate arid washing was concentrated under vacuum at 40-45°C to obtain solid residue which was stirred in ethyl acetate (750 mL) at 70-75°C for I h and then at 25-30°C for 12-14h. The solid was filtered, washed with ethyl acetate and dried under vacuum at 40-45°C for 12-14h to get title compound. Weight: 49.35 g Yield: 58.23% Purity: 99.91%
25 g With dmap In dichloromethane at 20℃; for 12h; 7; 8 Preparation of compound of formula I. Purification of Lacosamide To a stirred solution of formula (VIII) (27.7 grams) in anhydrous methylene dichloride (138 mL) is slowly added acetic anhydride (12.7 mL) and catalytic amount of dimethyl amino pyridine (0.5 grams). The resulting solution is stirred at RT for 12 hours. To the reaction mixture is added water (166 mL) and stirred for 15 minutes. The organic layer is successively washed with saturated sodium carbonate solution (83 mL). Organic layer is dried over sodium sulphate and solvent is evaporated to afford 31 grams of crude product of formula (I). The above obtained crude 31 grams is taken in EtOAc (217 mL) and mixture is refluxed for 30 minutes. Subsequently, reaction mixture is allowed to cool at 10°Cwhile maintaining the stirring for additional 30 minutes. The obtained crystalline mass is filtered and solid cake is washed with chilled EtOAc (31 mL). Obtained solid is dried under vacuum to afford 25 grams of Lacosamide with high chiral purity. *H - NMR (300 MHz, DMSO-d6): d= 8.47 (t, J=6.0Hz, 1H),8.08 (d, J=6.0Hz, 1H), 7.33 - 7.19 (m, 5H), 4.52 - 4.45 (m, 1H), 4.28 (d, J=6.0 Hz, 2H), 3.55 - 3.45 (m, 2H), 3.25 (s, 3H), 1.87 (s, 3H); MS(ESI): m/z =251.15 [M+H]+.
3.53 g In dichloromethane at 20℃; for 4h; 4.5. Synthesis of lacosamide Compound Id (3.38g, 16.2mmol) was dissolved in dichloromethane (35mL) and the resulting solution was treated with acetic anhydride (1.82g, 17.8mmol) after which the reaction mixture was stirred at ambient temperature for 4h. After completion of the reaction (indicated by TLC), the mixture washed with 5% aqueous sodium carbonate solution (20mL), followed by 10% aqueous citric acid solution (15mL), water (15mL), brine (10mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude product was dissolved in ethyl acetate (12mL), stirred at 70-75°C for 1h and then stirred at 25-30°C for 10h. The solid was filtered, washed with ethyl acetate (5mL) and dried under vacuum at 50°C for 6h to yield (R)-lacosamide as a colorless solid (3.53g, 87%); mp 143-44°C (lit.24 142-43°C); [α]D25=+16.0 (c 1, MeOH) {lit.24 [α]D20=+16.1 (c 1.2, MeOH)}; 99.88% purity by HPLC [Method: Hypersil BDS C 18, 4.6mm×250mm (5μm), water: CH3CN (80:20), Flow rate: 1.0mL/min, Detection: 210nm];% ee: 99.68% (Method-j, Table 1) [(R)-isomer Rt=8.90min; (S)-isomer Rt=10.45min]; IR (KBr, cm-1): vmax 3289, 3086, 3026, 3003, 2923, 2875, 1637, 1547, 1497, 1454, 1395, 1370, 1306, 1276, 1245, 1220, 1159, 1138, 1098, 945, 748, 694, 605; 1H NMR (300MHz, CDCl3): δH 2.02 (s, 3H), 3.37 (s, 3H), 3.41-3.46 (m, 1H), 3.78-3.82 (dd, J=9.0, 4.2Hz, 1H), 4.45-4.48 (m, 2H), 4.53-4.59 (m, 1H), 6.5 (br s, 1H), 6.82 (br s, 1H), 7.24-7.36 (m, 5H); 13C NMR (75MHz, CDCl3): δC 170.5, 170.1, 137.9, 128.5, 127.4, 127.3, 72.0, 58.9, 52.5, 43.4, 22.9; MS: m/z 250.9 [M+H]+.
for 0.5h; 4 Dichloromethane (625 L) was charged at room temperature, Lacosamide stage III product (130 kg), 30% concentrated hydrochloric acid (195 L) and water (260 L), reaction for 1 hour, extracted with 10% dilute hydrochloric acid solution (320 L), cool to 5 °C. The pH was adjusted to 9.5 with sodium hydroxide 2 solution. Extraction with dichloromethane, acetic anhydride (51.6 kg) was added, stirred for 30 minutes, extracted with water, after treatment with activated carbon, centrifuge and dry. i.e., obtain Lacosamide. Yield of about 96%.

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  • 2
  • [ 196601-68-0 ]
  • [ 196601-69-1 ]
YieldReaction ConditionsOperation in experiment
100% With hydrogen In methanol for 3h; Ambient temperature;
96% With hydrogen In methanol at 20℃; for 4h;
95% With palladium 10% on activated carbon; hydrogen at 20℃;
73% With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 5h;
With palladium 10% on activated carbon In ethyl acetate at 30 - 35℃; for 1h; 3.a (R)-N-benzyl-2-(benzyloxycarbonylamino)-3-methoxypropionamide (167 g, 458 mmol), (prepared as in example 1), was dissolved in ethyl acetate (1700 ml). To this solution was added Pd/C 10% (17 g). The resulting mixture was hydrogenated for 1 hour at 5-6 bar pressure at 30-35° C. The reaction mixture was then filtered to remove the catalyst. To the filtrate was added triethylamine (89.5 ml, 642 mmol) and acetic anhydride (51.9 ml, 550 mmol) in a dropwise manner. The resulting reaction mixture was stirred at room temperature for 1 hour. The product (R)-2-acetamido-N-benzyl-3-methoxypropionamide was isolated from ethyl acetate/n-heptane (1:1) mixture at 0-5° C. (98.7 g, 394.3 mmol, 86% Yields, HPLC purity 99.2 area %; ee>99.8%).
Stage #1: (R)-N-benzyl 2-N-(benzylcarboxycarbonyl)amino-3-methoxypropionamide With hydrogenchloride; water at 40 - 45℃; for 0.75h; Stage #2: With sodium hydroxide In water at 0 - 5℃; 25 ExampIe-25: Preparation of (R)-N-benzyl-2-amino-3-methoxypropionamide compound of formula-8:; A mixture of 2-N-(benzyloxycarbonyl) amino-3-methoxy propionamide (15 grams) and concentrated hydrochloric acid (150 ml) was heated to 40-45 °C and stirred for 45 mins. The reaction mixture was cooled to 0-5°C. Water (75 ml) was added to the reaction mixture and basified with aqueous sodium hydroxide solution. The reaction mixture is extracted into methylene chloride. The methylene chloride layer containing (R)-N-benzyl-2-amino-3-methoxypropionamide compound of formula-8 used directly in next step.

  • 3
  • [ 598-21-0 ]
  • [ 196601-69-1 ]
  • <i>N</i>-benzyl-2-(2-bromo-acetylamino)-3-methoxy-propionamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
78% With sodium hydrogencarbonate; sodium carbonate In dichloromethane at 5 - 10℃;
  • 4
  • [ 75-07-0 ]
  • [ 196601-69-1 ]
  • <i>N</i>-benzyl-2-ethylamino-3-methoxy-propionamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
51% With sodium cyanoborohydride In methanol at 20℃; for 0.166667h;
  • 5
  • [ 100-46-9 ]
  • [ 196601-69-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: 4-methylmorpholine / tetrahydrofuran / 0.03 h / -78 °C 1.2: isobutyl chloroformate / tetrahydrofuran / 0.03 h 1.3: 65 percent / tetrahydrofuran / -78 - 20 °C 2.1: 90 percent / Ag2O / acetonitrile / 20 °C 3.1: 96 percent / H2 / Pd/C / methanol / 4 h / 20 °C / 760 Torr
  • 6
  • [ 219835-31-1 ]
  • [ 196601-69-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 90 percent / Ag2O / acetonitrile / 20 °C 2: 96 percent / H2 / Pd/C / methanol / 4 h / 20 °C / 760 Torr
Multi-step reaction with 2 steps 1: 84 percent / Ag2O / acetonitrile / 72 h / Ambient temperature 2: 100 percent / H2 / 10percent Pd/C / methanol / 3 h / Ambient temperature
Multi-step reaction with 2 steps 1: silver(l) oxide / acetonitrile / 120 h / 20 °C 2: palladium 10% on activated carbon; hydrogen / methanol / 5 h / 20 °C / 760.05 Torr
Multi-step reaction with 2 steps 1.1: sodium hydroxide; tetrabutylammomium bromide / water; tert-butyl methyl ether / 12 h / -10 - 5 °C 2.1: hydrogenchloride; water / 0.75 h / 40 - 45 °C 2.2: 0 - 5 °C

  • 7
  • [ 100-46-9 ]
  • [ 196601-69-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: tetrahydrofuran / 1 h / Ambient temperature 2: 84 percent / Ag2O / acetonitrile / 72 h / Ambient temperature 3: 100 percent / H2 / 10percent Pd/C / methanol / 3 h / Ambient temperature
YieldReaction ConditionsOperation in experiment
1.f (f) (f) Enriched (R)-N-BENZYL-2-ACETAMIDO-3-METHOXYPROPIONAMIDE(II) To finish the synthesis in Scheme I, the following was performed. To a solution of I prepared hereinabove (0.20 g, 0.98 mmol) in dry THF (2.0 mL) is added pyridine (0.086 g, 1.08 mmol), and then acetic anhydride (0.2 g, 1.96 mmol) is added dropwise. The reaction is stirred at room temperature for 18 hours. The solvent is evaporated in vacuo and the residue purified by flash column chromatography to obtain the above compound. The compound formed was an approximate 85:15 enantiomeric mixture of the R and S stereoisomers, respectively.
YieldReaction ConditionsOperation in experiment
1.e (e) (e) Enriched (R)-N-BENZYL-2-AMINO-3-METHOXYPROPIONAMIDE(I) To a solution of 12 (122.8 mg, 0.36 mmol) in methanol (2.0 mL) was added 10% Pd-C (11 mg) and the mixture stirred at room temperature in the presence of H2 gas for 75 min. Celite was added to the reaction mixture and the catalyst was removed by filtration. The clear filtrate was evaporated in vacuo to give the compound of Formula I in the clear viscous oil (72 mg, 97%): Rf 0.30 (5% MeOH/CHCl3). The produce formed was an approximate 85:15 enantiomeric mixture of the R and S stereoisomers, respectively.
2.D EXAMPLE 2 D. (R)-N-BENZYL-2-AMINO-3-METHOXYPROPIONAMIDE (I). A MeOH (50 mL) solution of (R)-14 (1.00 g, 2.9 mmol) was hydrogenated in the presence of 10% Pd-C (0.20 g) at room temperature (3h). The mixture was filtered through Celite and the clear filtrate was evaporated in vacuo to obtain a pale yellow oil which O was purified by column chromatography (SiO2, 10% MeOH--CHCl3) to obtain the compound of Formula I as the R isomer (0.61 g, 100%) as a pale yellow oil: [α]23D (c=1.5, MeOH)=-2.0°; Rf 0.34 (10% MeOH--CHCl3); IR (liquid film) 3352, 3311, 3064, 2927, 2826, 1655, 1527, 1455, 1360, 1251, 1181, 1106, 971, 734, 700 cm-1; 1 H NMR (CDCl3) Δ 1.85 (br s, NH2), 3.34 (s, OCH3), 3.56-3.62 (m, CHOCH2), 4.39 (dd, J=6.0 15.2 Hz, NHCHH') 4.45 (dd, J=6.0, 15.2 Hz, NHCHH'), 7.20-7.36 (m, 10 PhH), 7.80-7.88 (m, NH); 13 C NMR (CDCl3) 43.1 (NHCH2) 54.9 (CH), 58.9 (OCH3), 74.6 (CH2 OCH3), 127.4 (C4 ') 127.6 (2C2 ' or 2C3 '), 128.6 (2C2 ' or 2C3 '), 138.4 (C1 ') 172.8 (C(O)) ppm; MS (+Cl) 209 (M+ +1); Mr (+Cl) 209.129 19 [M+ +1] calcd for C11 H17 N2 O2 209.129 00); Anal. (C11 H16 N2 O2 *0.15 H2 O) C,H,N.
  • 10
  • [ 880468-89-3 ]
  • [ 196601-69-1 ]
YieldReaction ConditionsOperation in experiment
100% With hydrogenchloride; water; In dichloromethane; at 0 - 30℃; for 2h; To a solution of (R)-tert-butyl-(1-(benzylamino)-3-rnethoxy-1-oxopropan-2- yl)carbamate (9.0 g) in methylene chloride (90 mL) was added concentrated hydrochloric acid (18.5 mL) at 0-5°C and stirred at 25-30°C for 2 hrs. Reaction mixture was diluted with water (20 mL) at 0-5°C and stirred for half an hour. The aqueous layer was basified with 20percent aqueous sodium hydroxide solution at 0-5°C and the reaction mixture was extracted in methylene chloride. The combined organic layer was washed with water and concentrated under vacuum to obtain the title compound. Weight: 6.1g Yield: 100percent,
100% With hydrogenchloride; water; In dichloromethane; at 0 - 30℃; for 2h; The above obtained Ic, (5.0g, 16.2mmol) was dissolved in dichloromethane (30mL) after which was added concentrated hydrochloric acid (3mL) at 0?5°C and stirred at 25?30°C for 2h. The reaction mixture was diluted with water (20mL), stirred for 10min and then both layers were separated. The aqueous layer pH was adjusted to 10 with 25percent NaOH, saturating with sodium chloride and extracted with dichloromethane (3×20mL). The organic layer was dried over Na2SO4, and evaporated under reduced pressure to yield (R)-2-amino-N-benzyl-3-methoxypropanamide Id as an oil (3.38g, 100percent). Compound Id was used directly in the next step without further purification.
100% With hydrogenchloride; In dichloromethane; water; at 0 - 10℃; for 1h; The above prepared compound of formula IV (30.8g, 0 . 100mol) dissolved in dichloromethane (31 ml), cooled to 0 °C, and in 0-10 °C by adding 36percent hydrochloric acid (48.7g, 0 . 500mol), in 0-10 °C reaction 1 hour later by adding dichloromethane (62 ml) extraction layered. In the aqueous layer by adding dichloromethane (155 ml), and in 0-10 °C with 20percent sodium hydroxide alkalise to pH= 10-12, the compound V obtains the type water/methylene chloride mixed solution (yield according to the 100percent meter, HPLC purity 97.1percent). The compounds of formula V need not be isolated,The mixed solution was used directly in the next step.
With hydrogenchloride; In dichloromethane; water; for 1h; To the C937 solution prepared above was added 36percent HCI (46.5ml, 0.541 mol) and the mixture aged for 1 hour. Water (66ml) was added and the phases separated. The organic phase was extracted with water (22ml) and the aqueous layers combined. The aqueous was basified to pH 10-12 with 30percent sodium hydroxide at <35°C and sodium chloride (8.8g) added. The aqueous layer was extracted with methylene chloride (2x110ml) and the combined organic layers washed with water (44ml) yielding a methylene EPO <DP n="20"/>chloride solution of (R)-2-amino-N-benzyl-3-methoxypropionamide.
Intermediate 6: Preparation of methoxypropanamideTo a cold solution (5° C.) of 3.36 g of Intermediate 5, benzylamide in 40 mL of dichloromethane was added 6.02 mL of 36percent HCl. The reaction mixture was stirred at room temperature until no starting material was observed by TLC. The organic phase was washed with 1N HCl (2.x.30 mL) and the combined aqueous phase basified to 10-12 with 25percent NaOH. After saturating the aqueous phase with sodium chloride, it was extracted with dichloromethane (3.x.30 mL). The organic phase was dried and concentrated under vacuum yielding 2.01 g of a pale yellow oil.
ExampIe-33: Preparation of (R)-N-benzyl-2-amino-3-methoxypropionamide compound of formula-8; Concentrated hydrochloric acid (175 ml) was added to a reaction mixture containing (R)-2-tert-butyl l-(benzylamino)-3-methoxy-l-oxopropan-2-yl carbonate (280 ml) obtained in example-32 at 0-5°C and stirred for 3 hrs. The organic and aqueous layers were separated. Aqueous layer was basified with sodium hydroxide and the reaction mixture extracted into methylene chloride. The methylene chloride layer containing the title compound used directly in the next step without any further isolation or purification.
Step 3:Production of (R)-2-amino-N-benzyI-3-methoxypropionamide.; <strong>[880468-89-3](R)-N-Benzyl-2-N-Boc-amino-3-methoxypropionamide</strong> solution in methylene chloride was concentrated till the solution volume was half of the original volume at 35-40°C under reduced pressure. Hydrochloric acid (36percent, 55 ml, 0.6137 mol) was added at 25-30°C and the resulting mixture was aged for 60-90 min at 25-30°C. Water (60 ml) was added and the phases were separated. The aqueous phase was washed with methylene chloride (50 ml). The aqueous layer was basified to pH 10-1 1 with 30percent sodium hydroxide at 25-30°C and saturated with sodium chloride (-20.0 g). The aqueous layer was extracted with methylene chloride (2 x 100 ml) . and the combined organic layer was dried over anhydrous sodium sulfate. Methylene chloride was distilled off at 35-40°C under diminished pressure to get oily mass. Yield: 40.0 g, HPLC purity: -94percent, Chiral purity: > 98percent.
3. Lacosamide ((R)-2-acetamido-N-benzyl-3-methoxypropionamide (I)) In a 1 L flask with overhead stirrer, condenser, thermometer and dropping funnel were combined 40 g (0.13 mol) (R)-boc-2-amino-N-benzyl-3-methoxy-propionamide (IV) and 400 ml dichloromethane. To this was carefully added 51.3g (0.52 mol) 37percent w/w hydrochloric acid in water. The reaction was stirred at 25 °C for 3 hours, at which time a sample showed >99percent hydrolysis of the boc protecting group. To the reaction was added 112 g water. The solution was then cooled on ice to 4-6 °C. With good mixing 75 g (0.62 mol) 33percent w/w sodium hydroxide solution in water was then slowly added maintaining the temperature between 4-8 °C. At completion of addition, 17.3 g (0.17 mol) acetic acid anhydride was slowly added. The reaction was allowed to come to room temperature and stirred for a further 1 hour. The phases were separated and the aqueous phase extracted with 100 ml dichloromethane. The dichloromethane phases were combined and washed with 25 ml water. The dichloromethane was then exchanged for toluene and lacosamide crystallised from a mixture of 460 ml toluene plus 10 ml methanol by warming until all solids were in solution and then slowly cooling to 4-8 °C. The lacosamide was filtered and washed 2 times with 50 ml toluene. Yield 24.8 g (76.4percent), purity by HPLC 99.9percent, ee >99.9percent, 1H NMR conforms. ee is enantiomeric excess and is calculated by determining the percentage of each separate enantiomer of a given chiral compound, such that the sum of the (R) and (S) enantiomers is 100percent, and subtracting one from the other.
3. Lacosamide ((R)-2-acetamido-N-benzyl-3-methoxypropionamide (I))In a 1 L flask with overhead stirrer, condenser, thermometer and dropping funnel were combined 40 g (0.13 mol) (R)-boc-2-amino-N-benzyl-3-methoxy-propionamide (IV) and 400 ml dichloromethane. To this was carefully added 51.3 g (0.52 mol) 37percent w/w hydrochloric acid in water. The reaction was stirred at 25° C. for 3 hours, at which time a sample showed >99percent hydrolysis of the boc protecting group. To the reaction was added 112 g water. The solution was then cooled on ice to 4-6° C. With good mixing 75 g (0.62 mol) 33percent w/w sodium hydroxide solution in water was then slowly added maintaining the temperature between 4-8° C. At completion of addition, 17.3 g (0.17 mol) acetic acid anhydride was slowly added. The reaction was allowed to come to room temperature and stirred for a further 1 hour. The phases were separated and the aqueous phase extracted with 100 ml dichloromethane. The dichloromethane phases were combined and washed with 25 ml water. The dichloromethane was then exchanged for toluene and lacosamide crystallised from a mixture of 460 ml toluene plus 10 ml methanol by warming until all solids were in solution and then slowly cooling to 4-8° C. The lacosamide was filtered and washed 2 times with 50 ml toluene. Yield 24.8 g (76.4percent), purity by HPLC 99.9percent, ee >99.9percent, 1H NMR conforms.
To the above solution of (i?)-N-benzyl-2-N-Boc-amino-3-methoxypropionamide in dichoromethane was added cone, hydrochloric acid and stirred at ambient temperature for 1 hour. Water was then added to the mixture, stirred and separated the product containing aqueous layer. Basified the aqueous layer to pH 10-12 and extracted with dichloromethane to obtain a solution of ( ?)-2-amino-N-benzyl-3- methoxypropionamide in dichloromethane
Preparation of (R)-2-amino-N-benzyl-3-methoxypropionamide(R)-N-Benzyl-2-((tert-butoxy)carbonylamino)-3-methoxypropionamide (116 gm) as obtained example 5 was dissolved in methylene chloride (1000 ml) and then added hydrochloric acid (36percent, 203 ml). The contents were maintained for 1 hour at room temperature and then added water (190 ml). The pH of the separated aqueous layer was adjusted to 10 to 11 with sodium hydroxide solution (30percent) and then extracted with methylene chloride. The solvent was distilled off to obtain a residual solid of (R)-2- amino-N-benzyl-3 -methoxypropionamide (62 gm).
Step II reaction mass (145 gm), dichloromethane (725 ml) and HCl (217.5 ml) were added at 27±3°C and stirred the reaction mass for 80-90 min. at 27±3°C. DM water was added 27±3°C and stirred for 5-10 min. at 27±3°C. The layers were separated. The organic layer was collected. The organic layer was washed with 10percent v/v HCl solution (29ml con HCl make 290 ml using DM water), stirred at 27±3°C for 5-10 min and allowed to settle. The combined aqueous layer was cooled to 0-5°C. Adjust pH 9-10 using 20percentw/v Sodium hydroxide solution at 0-15°C. Dichloromethane (725 ml) was added at 10-25°C and stirred for 5-10 min. at 27±3°C. The layers were separated. The organic layer was collected. The aqueous layer was extracted with dichloromethane (2x290 ml), stirred at 27±3°C and allowed to settle and layers were separated. Combined organic layers and sodium chloride solution (65.25 g in 435ml DM water) was added at 27±3°C and stirred for 10-15 min. at 27±3°C. The layers were separated. The organic layer (Product is in organic layer) was collected.
With hydrogenchloride; In dichloromethane; water; at 20℃; for 1h; To the above solution of <strong>[880468-89-3](R)-N-benzyl-2-N-Boc-amino-3-methoxypropionamide</strong> in dichoromethane was added conc. hydrochloric acid and stirred at ambient temperature for 1 hour. Water was then added to the mixture, stirred and separated the product containing aqueous layer. Basified the aqueous layer to pH 10-12 and extracted with dichloromethane to obtain a solution of (R)-2-amino-N-benzyl-3-methoxypropionamide in dichloromethane.
40.0 g With hydrogenchloride; In dichloromethane; water; at 25 - 40℃; Step 3 Production of (R)-2-amino-N-benzyl-3-methoxypropionamide <strong>[880468-89-3](R)-N-Benzyl-2-N-Boc-amino-3-methoxypropionamide</strong> solution in methylene chloride was concentrated till the solution volume was half of the original volume at 35-40° C. under reduced pressure. Hydrochloric acid (36percent, 55 ml, 0.6137 mol) was added at 25-30° C. and the resulting mixture was aged for 60-90 min at 25-30° C. Water (60 ml) was added and the phases were separated. The aqueous phase was washed with methylene chloride (50 ml). The aqueous layer was basified to pH 10-11 with 30percent sodium hydroxide at 25-30° C. and saturated with sodium chloride (?20.0 g). The aqueous layer was extracted with methylene chloride (2*100 ml) and the combined organic layer was dried over anhydrous sodium sulfate. Methylene chloride was distilled off at 35-40° C. under diminished pressure to get oily mass. Yield: 40.0 g, HPLC purity: ?94percent, Chiral purity: >98percent.
With hydrogenchloride; In dichloromethane; water; at 20℃; for 1h; Dichloromethane (625 L) was charged at room temperature, Lacosamide stage III product (130 kg), 30percent concentrated hydrochloric acid (195 L) and water (260 L), reaction for 1 hour, extracted with 10percent dilute hydrochloric acid solution (320 L), cool to 5 °C. The pH was adjusted to 9.5 with sodium hydroxide 2 solution. Extraction with dichloromethane.

  • 11
  • [ 1159573-88-2 ]
  • [ 196601-69-1 ]
YieldReaction ConditionsOperation in experiment
Stage #1: N-benzyl-O-methyl-N2-trityl-D-serinamide With hydrogenchloride In dichloromethane; water at 20℃; for 0.5h; Stage #2: With ammonia In water 4.a To a solution of Example 3 product (i.e. N-benzyl-O-methyl-N2-trityl-D-serinamide, 50 g) in dichloromethane (100 ml), hydrochloric acid (36%) was added at room temperature. This solution was stirred for 30 minutes at room temperature and then the solvent was completely recovered under vacuum at 40°C. Water (250 ml) was added to it at room temperature and the aqueous layer was neutralized with aqueous ammonia (20 ml). The aqueous layer was extracted with toluene (2 x 200 ml). The toluene was then completely recovered under vacuum at 50-55°C to get an oil. Yield = 15 gm.
Stage #1: N-benzyl-O-methyl-N2-trityl-D-serinamide With acetic acid In ethanol at 20℃; for 0.5h; Stage #2: With ammonia In water 4.b To a solution of Example 3 product (i.e., N-benzyl-O-methyl-N2-trityl-D-serinamide, 50 g) in absolute ethanol (100 ml), acetic acid (1.25 mole eq.) was added at room temperature. This solution was stirred for 30 minutes at room temperature and then the solvent was completely recovered under vacuum at 40°C. Water (250 ml) was added to it at room temperature and the aqueous layer was neutralized with aqueous ammonia (20 ml). The aqueous layer was extracted with toluene (2 x 200 ml). The toluene was then completely recovered under vacuum at 50-55°C to get an oil. Yield = 18 gm.
With hydrogenchloride In dichloromethane; water at 20℃; for 0.5h; 4.a Preparation of N-benzyl-O-methyl-D-serinamide Example 4a Preparation of N-benzyl-O-methyl-D-serinamide To a solution of Example 3 product (i.e. N-benzyl-O-methyl-N2-trityl-D-serinamide, 50 g) in dichloromethane (100 ml), hydrochloric acid (36%) was added at room temperature. This solution was stirred for 30 minutes at room temperature and then the solvent was completely recovered under vacuum at 40° C. Water (250 ml) was added to it at room temperature and the aqueous layer was neutralized with aqueous ammonia (20 ml). The aqueous layer was extracted with toluene (2*200 ml). The toluene was then completely recovered under vacuum at 50-55° C. to get an oil. Yield=15 gm.
With acetic acid In ethanol at 20℃; for 0.5h; 4.b Preparation of N-benzyl-O-methyl-D-serinamide Example 4b Preparation of N-benzyl-O-methyl-D-serinamide To a solution of Example 3 product (i.e., N-benzyl-O-methyl-N2-trityl-D-serinamide, 50 g) in absolute ethanol (100 ml), acetic acid (1.25 mole eq.) was added at room temperature. This solution was stirred for 30 minutes at room temperature and then the solvent was completely recovered under vacuum at 40° C. Water (250 ml) was added to it at room temperature and the aqueous layer was neutralized with aqueous ammonia (20 ml). The aqueous layer was extracted with toluene (2*200 ml). The toluene was then completely recovered under vacuum at 50-55° C. to get an oil. Yield=18 gm. Spectroscopic data of N-benzyl-O-methyl-D-serinamide IR (liq. film): 3352, 3311, 3064, 2964, 2927, 2826, 1655, 1527, 1455, 1360, 1251, 1181, 1106, 971, 734, 700 cm-1; 1H NMR (CDCl3) δ: 1.85 (br, s, NH2); 3.34 (s, OCH3) 3.56-3.62 (m, CHOCH2), 4.39 (dd, NHCH), 4.45 (dd, NHCH); 7.20-7.36 (m, 5 PhH) 7.80-7.88 (m, NH); MS (+CI): 209 (M++1).
Stage #1: N-benzyl-O-methyl-N2-trityl-D-serinamide With hydrogenchloride In dichloromethane; water at 25 - 30℃; Industry scale; Stage #2: With sodium hydroxide In water at 20 - 25℃; Industry scale; 4 Step 4: Preparation of N-benzyl-O-methyl-D-serinamideH2N(N-benzyl-O-methyl-D-serinamide)To the obtained organic layer as above, concentrated hydrochloric acid (6.2 Kg) was added at 25°C to 30°C in 15 to 20 minutes and the obtained reaction mixture was stirred for 60 minutes. De-ionized water (20 L) was added to the mixture and the layers were separated. The organic layer was washed with de-ionized water (20 L). The aqueous layer was washed with dichloromethane (10 L) and hexanes (20 L), respectively. The obtained aqueous layer was cooled to 20°C to 25°C and then the pH of this aqueous layer was adjusted to 1 1 to 11.5 by adding solution of sodium hydroxide (2.60 Kg in 26 L de-ionized water) into it. The aqueous layer was washed with hexanes (20 L) and the product was extracted with dichloromethane (3 X 40 L). The organic layers were combined and washed with de-ionized water (40 L). The layers were separated and the organic layer (dichloromethane layer) was collected.
Stage #1: N-benzyl-O-methyl-N2-trityl-D-serinamide With hydrogenchloride; water In dichloromethane at 25 - 30℃; Stage #2: With sodium hydroxide In hexanes; water at 20 - 25℃; 1.2.2C Step 2C: In-situ preparation of N-benzyl-0-methyl-D-serinamide; To the organic layer (the dichloromethane layer) as obtained above, concentrated hydrochloric acid (23.22 g dissolved in 65 ml de-ionized water) was added in 15 minutes to 20 minutes at 25 °C to 30°C. It was stirred for 60 minutes at the same temperature and allowed to settle for 15 minutes. The layers were separated. The organic and aqueous layers were separately collected. To the organic layer, de-ionized water (65 ml) was added, stirred and allowed to settle for 15 minutes. Again, the layers were separated and the organic and aqueous layers were separately collected. Both aqueous layers obtained were combined and dichloromethane (32.5 ml) was added at 25°C to 30°C, stirred and allowed to settle for 15 minutes. The layers were separated and collected separately. From the aqueous layer, traces of dichloromethane were recovered under vacuum at 30°C to 35°C. The aqueous layer was cooled to 25°C to 30°C and then filtered through a 0.45 micron filter. To the filtered layer, hexanes (65 ml) were added at ambient temperature, stirred and allowed to settle for 15 minutes. These layers were separated. The aqueous layer was again separated and cooled to 20°C to 25°C. The pH of the aqueous layer was adjusted to 11 to 11.5 by using 10% sodium hydroxide solution (88 ml) at 20°C to 25°C.

  • 12
  • [ 108-24-7 ]
  • [ 196601-69-1 ]
  • (2S)-2-(acetylamino)-N-benzyl-3-methoxypropanamide [ No CAS ]
  • lacosamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
In dichloromethane at 20℃; for 2h; 3.2 1 ,12 g (R)-2-amino-N-benzyl-3-methoxy-propionamide (IVa) (0,0054 mol) is dissolved in 25 ml of dichloromethane. After adding 0,756 ml acetic anhydride (0,8167 g, 0,08 mol), the mixture was stirred for 2 hours at room temperature. Subsequently, the mixture was consecutively extracted with 5 ml water, 5 ml 1 M hydrochloric acid, 5 ml 5% sodiumhydrogencarbonate-solution and 5 ml water. The organic product phase is evaporated (HPLC: R-lsomer: 93,46% (I), S-lsomer: 6,54% (III)).
  • 13
  • C12H18N2O2 [ No CAS ]
  • [ 108-24-7 ]
  • [ 196601-69-1 ]
  • C14H20N2O3 [ No CAS ]
  • lacosamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine In ethyl acetate at 20℃; for 1h; 4.a (R)-N-benzyl-2-(benzyloxycarbonylamino)-3-methoxypropionamide (4 g, 11.7 mmol), (prepared in example 4), was dissolved in ethyl acetate (50 ml). To this solution was added Pd/C 10% (0.5 g). The resulting mixture was hydrogenated for 5.5 hours at 5 bar pressure at 30-35° C. The reaction mixture was then filtrated to separate the catalyst. To the filtrate was added triethylamine (2.31 ml, 16.6 mmol) and acetic anhydride (1.35 ml, 14.3 mmol) and the resulting reaction mixture was stirred at room temperature for 1 hour. The product (R)-2-acetamido-N-benzyl-3-methoxypropionamide was isolated from ethyl acetate/heptane (1:1) mixture at 0-5° C. (1.47 mg, 5.9 mmol, 50.3%, [α]D+15.5°; HPLC purity 99.4%; ee>99.8%). Mother liquor was evaporated till dryness (2.13 g, HPLC purity Lacosamide 69.4 area %, N-Me Lacosamide 20.0 area %; assay 67%).
  • 14
  • C20H24N2O4 [ No CAS ]
  • [ 196601-68-0 ]
  • C12H18N2O2 [ No CAS ]
  • [ 196601-69-1 ]
YieldReaction ConditionsOperation in experiment
With palladium 10% on activated carbon In ethyl acetate at 30 - 35℃; for 1h; 4.a (R)-N-benzyl-2-(benzyloxycarbonylamino)-3-methoxypropionamide (4 g, 11.7 mmol), (prepared in example 4), was dissolved in ethyl acetate (50 ml). To this solution was added Pd/C 10% (0.5 g). The resulting mixture was hydrogenated for 5.5 hours at 5 bar pressure at 30-35° C. The reaction mixture was then filtrated to separate the catalyst. To the filtrate was added triethylamine (2.31 ml, 16.6 mmol) and acetic anhydride (1.35 ml, 14.3 mmol) and the resulting reaction mixture was stirred at room temperature for 1 hour. The product (R)-2-acetamido-N-benzyl-3-methoxypropionamide was isolated from ethyl acetate/heptane (1:1) mixture at 0-5° C. (1.47 mg, 5.9 mmol, 50.3%, [α]D+15.5°; HPLC purity 99.4%; ee>99.8%). Mother liquor was evaporated till dryness (2.13 g, HPLC purity Lacosamide 69.4 area %, N-Me Lacosamide 20.0 area %; assay 67%).
  • 15
  • [ 144-62-7 ]
  • [ 196601-69-1 ]
  • (R)-N-benzyl-2-amino-3-methoxypropionamide oxalate [ No CAS ]
YieldReaction ConditionsOperation in experiment
In isopropyl alcohol at 0 - 32℃; for 1.25h; 35 Example-35: Preparation of (R)-N-benzyl-2-amino-3-methoxypropionamide oxalate compound of formuIa-19a:; A solution of oxalic acid (2.1 grams) in isopropyl alcohol (5 ml) was added to a solution of (R)-N-benzyl-2-amino-3-methoxypropionamide having purity of 91.8% (5 grams) in isopropyl alcohol(10 ml) at 25-32°C and stirred for 15 minutes. The reaction mixture was cooled to 0-5° and stirred for 30 min. Then the reaction mixture was stirred for 30 minutes at 10-15°C. The solid obtained was filtered, washed with isopropyl alcohol and dried to get the title compound.Yield: 2.5 gramsPurity by HPLC: 97%
  • 16
  • (R)-N-benzyl-2-amino-3-methoxypropionamide oxalate [ No CAS ]
  • [ 196601-69-1 ]
YieldReaction ConditionsOperation in experiment
With sodium hydroxide In water 36 Example-36: Preparation of highly pure (R)-N-benzyI-2-amino-3-methoxy propionamide compound of formuIa-8:; Water (10 ml) was added to (R)-N-benzyl-2-amino-3-methoxy propionamide oxalate compound of formula- 19a (1 gram) and the reaction mixture was basified with sodium hydroxide solution. Extracted the reaction with methylene chloride and distilled off the methylene chloride layer to get the title compound.Yield: 0.6 gramsPurity by HPLC: 96.8%
  • 17
  • [ 100-46-9 ]
  • [ 196601-69-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: 4-methyl-morpholine; isobutyl chloroformate / dichloromethane / -5 °C 1.2: -5 - 0 °C 2.1: potassium hydroxide / dichloromethane / 5 °C 2.2: 5 °C 3.1: hydrogenchloride / dichloromethane; water / 25 - 30 °C 3.2: 25 - 30 °C / pH 10 - 11
Multi-step reaction with 3 steps 1.1: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; 4-methyl-morpholine / ethyl acetate / 3.5 h / 4 - 25 °C / Inert atmosphere 2.1: sodium hydroxide / tetra(n-butyl)ammonium hydrogensulfate / dichloromethane; water / 4 - 25 °C / Inert atmosphere 3.1: hydrogenchloride; water / dichloromethane / 3 h / 25 °C 3.2: 4 - 8 °C
Multi-step reaction with 3 steps 1.1: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; 4-methyl-morpholine / ethyl acetate / 3.5 h / 4 - 25 °C / Cooling with ice; Inert atmosphere 2.1: tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide / dichloromethane; water / 4 - 25 °C / Cooling with ice; Inert atmosphere 3.1: hydrogenchloride; water / dichloromethane / 3 h / 25 °C 3.2: 4 - 8 °C
Multi-step reaction with 3 steps 1.1: methyl chloroformate; 4-methyl-morpholine / dichloromethane / 0.5 h / 35 °C 1.2: 20 °C 2.1: sodium hydroxide; tetrabutylammomium bromide / toluene; water / 2 - 27 °C 3.1: hydrogenchloride / dichloromethane; water / 27 °C 3.2: 0 - 15 °C
Multi-step reaction with 3 steps 1.1: isobutyl chloroformate; 4-methyl-morpholine / dichloromethane / 5 °C 1.2: 0 - 5 °C 2.1: potassium hydroxide / 5 °C 2.2: 5 °C 3.1: hydrogenchloride / dichloromethane; water / 25 - 40 °C
Multi-step reaction with 2 steps 1: 3 h / 20 °C 2: water; hydrogenchloride / dichloromethane / 2 h / 0 - 30 °C
Multi-step reaction with 2 steps 1.1: triethylamine / acetonitrile / 0.17 h / -15 °C 1.2: 0.17 h 2.1: sodium hydroxide; 3-hydroxypropionamide / -5 - 5 °C

  • 18
  • [ 1253790-58-7 ]
  • [ 196601-69-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: potassium hydroxide / dichloromethane / 5 °C 1.2: 5 °C 2.1: hydrogenchloride / dichloromethane; water / 25 - 30 °C 2.2: 25 - 30 °C / pH 10 - 11
Multi-step reaction with 2 steps 1.1: sodium hydroxide / tetra(n-butyl)ammonium hydrogensulfate / dichloromethane; water / 4 - 25 °C / Inert atmosphere 2.1: hydrogenchloride; water / dichloromethane / 3 h / 25 °C 2.2: 4 - 8 °C
Multi-step reaction with 2 steps 1.1: tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide / dichloromethane; water / 4 - 25 °C / Cooling with ice; Inert atmosphere 2.1: hydrogenchloride; water / dichloromethane / 3 h / 25 °C 2.2: 4 - 8 °C
Multi-step reaction with 2 steps 1.1: sodium hydroxide / tetrabutylammomium bromide / dichloromethane; water / 2 h / 5 - 20 °C 2.1: hydrogenchloride; water / dichloromethane / 1 h / 20 °C 2.2: pH 10 - 12 / Alkaline aqueous solution
Multi-step reaction with 4 steps 1.1: hydrogenchloride / dichloromethane; water / 20 - 25 °C 1.2: pH 8 - 9 2.1: triethylamine / tetrahydrofuran 3.1: potassium hydroxide; tetrabutylammomium bromide / ethyl acetate 4.1: hydrogenchloride / water / Reflux 4.2: pH 8 - 9
Multi-step reaction with 2 steps 1.1: sodium hydroxide; tetrabutylammomium bromide / toluene; water / 2 - 27 °C 2.1: hydrogenchloride / dichloromethane; water / 27 °C 2.2: 0 - 15 °C
Multi-step reaction with 5 steps 1: hydrogenchloride; water / dichloromethane / 20 - 25 °C 2: sodium hydroxide / water / 20 - 25 °C / pH 8 - 9 3: triethylamine / tetrahydrofuran 4: tetrabutylammomium bromide; potassium hydroxide / ethyl acetate 5: hydrogenchloride; water / Reflux
Multi-step reaction with 2 steps 1: sodium hydroxide; tetrabutylammomium bromide / dichloromethane / 2 h / 5 - 20 °C 2: hydrogenchloride / water; dichloromethane / 1 h / 20 °C
Multi-step reaction with 2 steps 1.1: potassium hydroxide / 5 °C 1.2: 5 °C 2.1: hydrogenchloride / dichloromethane; water / 25 - 40 °C
Multi-step reaction with 2 steps 1: sodium hydroxide; tetrabutylammomium bromide / water; toluene / 1.5 h / 0 - 30 °C 2: hydrogenchloride / water; dichloromethane / 1 h / 20 °C

  • 19
  • [ 1346691-15-3 ]
  • [ 196601-69-1 ]
YieldReaction ConditionsOperation in experiment
With hydrogen In methanol at 25 - 30℃; for 8h; Inert atmosphere; 3.5 Step 5:; Preparation of (2R)-2-amino 3-methoxypropanomide (O-methyl D-serinamide); N,N-dibenzyl-0-methyl-D-serinamide (25 g, 0.0644 mol) was dissolved in methanol (160 ml) at 27-30°C. Palladium hydroxide (10%, 9 g) was added under nitrogen atmosphere. The reaction mass was subjected to parr under hydrogen pressure 5 Kg / Cm at 25-30°C for 8 h.The reaction mass was filtered through hyflo and washed the bed with methanol (50 ml). The filtrate mother liquors were concentrated under reduced pressure to get a colourless oily mass.Yield: 13 g (Crude).
With hydrogen; palladium(II) hydroxide In methanol at 25 - 30℃; for 8h; Inert atmosphere; 3.5 Preparation of (2R)-2-amino 3-methoxypropanomide (O-methyl D-serinamide) Preparation of (2R)-2-amino 3-methoxypropanomide (O-methyl D-serinamide) [0124] N,N-dibenzyl-O-methyl-D-serinamide (25 g, 0.0644 mol) was dissolved in methanol (160 ml) at 27-30° C. Palladium hydroxide (10%, 9 g) was added under nitrogen atmosphere. The reaction mass was subjected to parr under hydrogen pressure 5 Kg/Cm2 at 25-30° C. for 8 h. The reaction mass was filtered through hyflo and washed the bed with methanol (50 ml). The filtrate mother liquors were concentrated under reduced pressure to get a colourless oily mass. Yield: 13 g (Crude).
  • 20
  • [ 1253790-58-7 ]
  • [ 77-78-1 ]
  • [ 196601-69-1 ]
YieldReaction ConditionsOperation in experiment
90.71% Stage #1: tert-butyl-N-[(1R)-2-(benzylamino)-1-(hydroxymethyl)-2-oxo-ethyl]carbamate; dimethyl sulfate With water; sodium hydroxide In dichloromethane at -10 - -5℃; Stage #2: With hydrogenchloride In dichloromethane; water at 25 - 30℃; for 2h; 7 Example - 7: Preparation of (2fl)-2-amino-N-benzyl-3-methoxypropanamide.In a reaction flask charged tert-butyl [(li?)-2-(benzylamino)-l-(hydroxymethyl)-2- oxoethyl]carbamate (110.0 gms) and tetrabutylammonium bromide (18.07gms) in solvent •dichloromethane (550ml), stirred and cooled to -10°C.Charged aqueous solution of sodium hydroxide (75.0 gms in 195 ml of DM water) maintaining temperature at -10°C to -5°C. Charged slowly within lhour, dimethyl sulfate (141.4 gms) maintaining temperature at -10°C to -5°C and maintained the reaction mass at -10°C to -5°C for 3.5 to 4.5hrs. After completion of the reaction, charged DM water (550ml) and stirred for 15 minutes at 25 - 30°C Separated the organic layer and charged in the reaction flask. Charged cone. Hydrochloric acid (440ml) within 15 min and maintained the reaction mixture at 25 - 30°C for 1 - 2 hours. After completion of 2 hours charged DM water (330ml) and stirred for 20 - 25 minutes. Separated the organic layer and washed with DM water (330ml). Combined both aqueous layers and cooled to 15 - 20°C to adjust pH of the solution to 13 - 14 with the help of 50 % sodium hydroxide solution. Extracted the aqueous layer with dichloromethane (1 x 550ml, 2 x 330ml). Combined all , dichloromethane layers and washed with DM water and stirred at 25-30°C for 10 - 15 minutes. Charcoalised dichloromethane layer at 25 - 30°C for 30 minutes, filtered and washed the hyflow bed with dichloromethane (2 x 1 10ml). Concentrated the filtrate under reduced pressure below 40°C and degas under vacuum at 35-40°C for 3 - 4hrs to get oily mass of (2i?)-2-Amino-N-benzyl-3-methoxypropanamide.Yield= 70.6 gms% Yield= 90.71%.
  • 21
  • [ 175481-39-7 ]
  • [ 196601-69-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: ethyl acetate / 1 h / 25 - 30 °C 1.2: 1 h / 25 - 30 °C 2.1: sodium hydroxide; water / tetrabutylammomium bromide / dichloromethane / -10 - -5 °C 2.2: 2 h / 25 - 30 °C
Multi-step reaction with 3 steps 1.1: triethylamine / tetrahydrofuran 2.1: potassium hydroxide; tetrabutylammomium bromide / ethyl acetate 3.1: hydrogenchloride / water / Reflux 3.2: pH 8 - 9
Multi-step reaction with 3 steps 1: triethylamine / tetrahydrofuran 2: tetrabutylammomium bromide; potassium hydroxide / ethyl acetate 3: hydrogenchloride; water / Reflux
  • 22
  • [ 1357171-71-1 ]
  • [ 196601-69-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: hydrogen / 5%-palladium/activated carbon / ethyl acetate / 1 h / 25 - 30 °C / 2795.17 Torr / Autoclave 2.1: ethyl acetate / 1 h / 25 - 30 °C 2.2: 1 h / 25 - 30 °C 3.1: sodium hydroxide; water / tetrabutylammomium bromide / dichloromethane / -10 - -5 °C 3.2: 2 h / 25 - 30 °C
  • 23
  • [ 1357171-70-0 ]
  • [ 196601-69-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: sodium azide / N,N-dimethyl-formamide / 50 - 55 °C 2.1: hydrogen / 5%-palladium/activated carbon / ethyl acetate / 1 h / 25 - 30 °C / 2795.17 Torr / Autoclave 3.1: ethyl acetate / 1 h / 25 - 30 °C 3.2: 1 h / 25 - 30 °C 4.1: sodium hydroxide; water / tetrabutylammomium bromide / dichloromethane / -10 - -5 °C 4.2: 2 h / 25 - 30 °C
  • 24
  • [ 75-36-5 ]
  • [ 196601-69-1 ]
  • lacosamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
62.4% With triethylamine at 10 - 25℃; 6 Embodiment 6; Preparation of (R)-2-acetylamino-N-benzyl-3-methoxypropionamide To a 100 mL three-neck round bottom flask, the organic obtained in Embodiment 5 and 2.22 g (0.022 mol) triethylamine were added, and the temperature was decreased to 10° C. At 10-25° C., 1.73 g (0.022 mol) acetyl chloride was added slowly. After addition, the reaction was continued, till the raw materials were completely converted. After the reaction was completed, the reaction liquid was washed with 40 g×2 saturated sodium bicarbonate solution. The solvent was evaporated, to obtain 3.92 g white solid. The product was recrystallized with an n-hexane-ethyl acetate mixture solvent, to obtain a white powder solid of 3.12 g (0.0125 mol). The molar yield was 62.4% (with respect to (R)-N-benzyl-2-(ethoxycarbonylamino)-3-methoxypropionamide).
3.12 g With triethylamine In dichloromethane at 10 - 25℃; 6 Preparation of (R)-2-acetylamino-N-benzyl-3-methoxypropionamide To a 100 mL three-neck round bottom flask, the organic obtained in Embodiment 5 and 2.22 g (0.022 mol) triethylamine were added, and the temperature was decreased to 10° C. At 10-25° C., 1.73 g (0.022 mol) acetyl chloride was added slowly. After addition, the reaction was continued, till the raw materials were completely converted. After the reaction was completed, the reaction liquid was washed with 40 g×2 saturated sodium bicarbonate solution. The solvent as evaporated, to obtain 3.92 g white solid. The product was recrystallized with an n-hexane-ethyl acetate mixture solvent, to obtain a white powder solid of 3.12 g (0.0125 mol). The molar yield was 62.4% (with respect to (R)-N-benzyl-2-(ethoxycarbonylamino)-3-methoxypropionamide).
935 mg With sodium carbonate In toluene at 0 - 5℃; for 1h; Inert atmosphere;
935 mg With sodium carbonate In toluene at 0 - 5℃; for 1h; Preparation of the Final Product (R)-Lacosamide (FIG. 1, No. B) To a solution of the compound (R)-N-Benzyl-2-(isoindolin-2-yl)-3-methoxypropanamide (, No. 6) (1.4 g, 4.1 mmol) in 20 mL of isopropyl alcohol was added hydrazine monohydrate (0.22 mL, 4.5 mmol) at 0° C. under nitrogen atmosphere. The reaction was stirred at 25° C. for 2 h. The resulting solution was filtered, washed with diethyl ether, brine, dried over magnesium sulphate and concentrated in vacuo to furnish the crude compound [Rf=0.36, CH2Cl2:MeOH (9:1)]. The resulting crude was used as such for the next step without further purification. The residue was then dissolved in dry toluene followed by addition of Na2CO3 (1.3 g, 12.3 mmol) was added. The reaction mixture was cooled to 0° C. after which acetyl chloride (0.33 mL, 4.5 mmol) was slowly added and the solution stirred at 5° C. for 1 h. After completion of the reaction, the solid was filtered through a celite pad and the solvent was evaporated in vacuo. The crude product was purified by silica gel column chromatography (CH2Cl2:MeOH, 95:05) to afford 935 mg (91%) yield of (R)-Lacosamide (, No. B) as white solid [Rf=0.47, CH2Cl2:MeOH (9:1)]; mp 143-144° C. [Lit. 140-141° C., 142-143° C.]; [α]D25 +16.1 (c 1, MeOH) [Lit. +16.2 (c 1, MeOH), +16.1 (c 1.2, MeOH),]; IR (CH2Cl2) v: 3054, 2928, 1650, 1529, 1372, 1264, and 1118 cm-1; 1H NMR (400 MHz, CDCl3) δ:2.02 (s, 3H), 3.37 (s, 3H), 3.44 (m, 1H), 3.80 (m, 1H), 4.47 (m, 2H), 4.57 (m, 1H), 6.54 (s, 1H), 6.86 (s, 1H), 7.24-7.68 (m, 5H); 13C NMR (100 MHz, CDCl3) δ: 23.2, 43.5, 52.3, 59.0, 71.6, 127.4, 127.4, 128.7, 137.8, 169.9, 170.3.
108 mg With triethylamine at 0 - 20℃; for 1.58333h; Inert atmosphere;

  • 25
  • [ 1320360-91-5 ]
  • [ 196601-69-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: potassium hydroxide; tetrabutylammomium bromide / ethyl acetate 2.1: hydrogenchloride / water / Reflux 2.2: pH 8 - 9
Multi-step reaction with 2 steps 1: tetrabutylammomium bromide; potassium hydroxide / ethyl acetate 2: hydrogenchloride; water / Reflux
  • 26
  • [ 1320360-92-6 ]
  • [ 196601-69-1 ]
YieldReaction ConditionsOperation in experiment
Stage #1: (R)-N-benzyl-2-(ethoxycarbonylamino)-3-methoxypropionamide With hydrogenchloride In water Reflux; Stage #2: With sodium hydroxide In water 5 Embodiment 5; Preparation of (R)-2-amino-N-benzyl-3-methoxypropionamide To a 100 mL single-neck flask, 5.6 g (0.02 mol) (R)-N-benzyl-2-(ethoxycarbonylamino)-3-methoxypropionamide and 50 mL 31% concentrated hydrochloric acid were added, the mixture was heated and refluxed for 6-10 hr. After the reaction as completed, 30% sodium hydroxide solution was added to adjust the pH value of the system to 8-9. The reaction liquid was extracted with 50 mL×2 dichloromethane, and dried over anhydrous sodium sulfate. The product can be directly used in following synthesis without further purification.
With hydrogenchloride; water Reflux; 5 Preparation of (R)-2-amino-N-benzyl-3-methoxypropionamide To a 100 mL single-neck flask, 5.6 g (0.02 mol) (R)-N-benzyl-2-(ethoxycarbonylamino)-3-methoxypropionamide and 50 mL 31% concentrated hydrochloric acid were added, the mixture was heated and refluxed for 6-10 hr. After the reaction was completed, 30% sodium hydroxide solution was added to adjust the pH value of the system to 8-9. The reaction liquid was extracted with 50 mL×2 dichloromethane, and dried over anhydrous sodium sulfate. The product can be directly used in following synthesis without further purification.
  • 27
  • [ 1322062-75-8 ]
  • [ 196601-69-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: sodium hydroxide / water / 20 - 25 °C / pH 8 - 9 2: triethylamine / tetrahydrofuran 3: tetrabutylammomium bromide; potassium hydroxide / ethyl acetate 4: hydrogenchloride; water / Reflux
  • 28
  • N-benzyl-2-amino-3-methoxypropanamide N-formyl-L-leucine salt [ No CAS ]
  • [ 196601-69-1 ]
YieldReaction ConditionsOperation in experiment
1.59 g With alkaline salt solution In dichloromethane; water 1 Example 1 Isolation of (R)-2-amino-N-benzyl-3-methoxypropanamide without the use of a racemiser 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.
  • 29
  • [ 108-22-5 ]
  • [ 196601-69-1 ]
  • lacosamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
68.9% In Isopropyl acetate at 23 - 75℃; 3 Example 3 Acetylation of (R)-2-amino-N-benzyl-3-methoxypropanamide 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%.
  • 30
  • (R)-tert-butyl (1-(benzylamino)-3-methoxy-1-oxopropan-2-yl)-N-(hydroxymethyl)carbamate [ No CAS ]
  • [ 196601-69-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: tert-butyl methyl ether / 60 - 65 °C 2: hydrogenchloride; water / dichloromethane / 2 h / 0 - 30 °C
  • 31
  • (R)-N-benzyl-2-(isoindolin-2-yl)-3-methoxypropanamide [ No CAS ]
  • [ 196601-69-1 ]
YieldReaction ConditionsOperation in experiment
With hydrazine hydrate In isopropyl alcohol at 0 - 25℃; for 2h; Inert atmosphere;
With hydrazine hydrate In isopropyl alcohol at 0 - 25℃; for 2h; Inert atmosphere; Preparation of the Final Product (R)-Lacosamide (FIG. 1, No. B) To a solution of the compound (R)-N-Benzyl-2-(isoindolin-2-yl)-3-methoxypropanamide (, No. 6) (1.4 g, 4.1 mmol) in 20 mL of isopropyl alcohol was added hydrazine monohydrate (0.22 mL, 4.5 mmol) at 0° C. under nitrogen atmosphere. The reaction was stirred at 25° C. for 2 h. The resulting solution was filtered, washed with diethyl ether, brine, dried over magnesium sulphate and concentrated in vacuo to furnish the crude compound [Rf=0.36, CH2Cl2:MeOH (9:1)]. The resulting crude was used as such for the next step without further purification. The residue was then dissolved in dry toluene followed by addition of Na2CO3 (1.3 g, 12.3 mmol) was added. The reaction mixture was cooled to 0° C. after which acetyl chloride (0.33 mL, 4.5 mmol) was slowly added and the solution stirred at 5° C. for 1 h. After completion of the reaction, the solid was filtered through a celite pad and the solvent was evaporated in vacuo. The crude product was purified by silica gel column chromatography (CH2Cl2:MeOH, 95:05) to afford 935 mg (91%) yield of (R)-Lacosamide (, No. B) as white solid [Rf=0.47, CH2Cl2:MeOH (9:1)]; mp 143-144° C. [Lit. 140-141° C., 142-143° C.]; [α]D25 +16.1 (c 1, MeOH) [Lit. +16.2 (c 1, MeOH), +16.1 (c 1.2, MeOH),]; IR (CH2Cl2) v: 3054, 2928, 1650, 1529, 1372, 1264, and 1118 cm-1; 1H NMR (400 MHz, CDCl3) δ:2.02 (s, 3H), 3.37 (s, 3H), 3.44 (m, 1H), 3.80 (m, 1H), 4.47 (m, 2H), 4.57 (m, 1H), 6.54 (s, 1H), 6.86 (s, 1H), 7.24-7.68 (m, 5H); 13C NMR (100 MHz, CDCl3) δ: 23.2, 43.5, 52.3, 59.0, 71.6, 127.4, 127.4, 128.7, 137.8, 169.9, 170.3.
  • 32
  • C10H12ClNO2 [ No CAS ]
  • [ 196601-69-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: methanol / 3 h / 0 - 20 °C / Inert atmosphere 2: triethylamine; dmap / dichloromethane / 12 h / 20 °C / Inert atmosphere; Cooling with ice 3: sodium azide / water; N,N-dimethyl-formamide / 6 h / 70 °C / Inert atmosphere 4: 5%-palladium/activated carbon; hydrogen / methanol / 3 h / 20 °C / Autoclave
  • 33
  • [ 1567820-75-0 ]
  • [ 196601-69-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: triethylamine; dmap / dichloromethane / 12 h / 20 °C / Inert atmosphere; Cooling with ice 2: sodium azide / water; N,N-dimethyl-formamide / 6 h / 70 °C / Inert atmosphere 3: 5%-palladium/activated carbon; hydrogen / methanol / 3 h / 20 °C / Autoclave
  • 34
  • [ 1567820-77-2 ]
  • [ 196601-69-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: sodium azide / water; N,N-dimethyl-formamide / 6 h / 70 °C / Inert atmosphere 2: 5%-palladium/activated carbon; hydrogen / methanol / 3 h / 20 °C / Autoclave
  • 35
  • (R)-2-azido-N-benzyl-3-methoxypropanamide [ No CAS ]
  • [ 196601-69-1 ]
YieldReaction ConditionsOperation in experiment
With 5%-palladium/activated carbon; hydrogen In methanol at 20℃; for 3h; Autoclave; 6 Preparation of compound of Formula VIII The obtained crude of formula (VII) (33 grams) is dissolved in methanol (150 mL) and to the reaction mixture in autoclave is added 5%palladium carbon (4.2 grams) at RT under nitrogen atmosphere. The reaction mixture is stirred for 3 hours at RT under 3 kg H2 gas pressure. TLC (50% EtOAc in n-hexane) showed complete consumption of staring material and formation of slower moving spot. Filter the reaction mixture through celite pad and the celite pad is washed successively with hot methanol (30 mL). The solvent is then evaporated at RT and the temperature is raised to 50 °C towards the end of evaporation to remove residual solvent. The crude product of formula (VIII) (28 grams) is considered for subsequent stage without further purification. *H - NMR (300 MHz, DMSO-d6): d= 8.39 (s, 1H), 7.33 - 7.20 (m, 5H), 4.30 (dd, J = 6.0 Hz, 3.0Hz, 2H), 3.45 - 3.39 (m, 3H), 3.25 (s, 3H), 1.97 (s, 2H). MS(ESI):m/z=209.17 [M+H]+.
  • 36
  • [ 86118-11-8 ]
  • [ 100-46-9 ]
  • [ 196601-69-1 ]
  • [ 474534-78-6 ]
YieldReaction ConditionsOperation in experiment
88 % ee With tris(2,2,2-trifluoroethyl) borate at 125℃; for 4h;
  • 37
  • [ 38117-54-3 ]
  • [ 54245-42-0 ]
  • [ 196601-69-1 ]
  • [11C]lacosamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
52 %Chromat. With dichloro[9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene]palladium (II) In tetrahydrofuran at 0 - 160℃; for 0.166667h; Sealed tube; Inert atmosphere;
  • 38
  • [ 77-78-1 ]
  • [ 175481-39-7 ]
  • [ 196601-69-1 ]
YieldReaction ConditionsOperation in experiment
With 3-hydroxypropionamide; sodium hydroxide at -5 - 5℃; 2 The solution of the hydroxypropionamide solution of Example 1 and 266 g of 30% sodium hydroxide solution, 120 g of dimethyl sulfate solution were first introduced into the control unit of the hydroxypropionamide solution of the temperature control unit, the sodium hydroxide solution temperature control unit, the dimethyl sulfate Solution temperature control Unit, the control temperature of -5 ~ 5 , and then into the reaction unit 1 reaction 10-20 minutes, after the reaction out of the micro-reactor, And extracted with methylene chloride to give methylene chloride solution of methoxypropionamide.
  • 39
  • [ 19794-53-7 ]
  • [ 100-46-9 ]
  • [ 196601-69-1 ]
  • [ 474534-78-6 ]
  • 40
  • C17H19N3O4 [ No CAS ]
  • [ 196601-69-1 ]
YieldReaction ConditionsOperation in experiment
95% Stage #1: C17H19N3O4 With 5%-palladium/activated carbon; hydrogen In ethyl acetate at 20℃; for 4h; Stage #2: With [bis(acetoxy)iodo]benzene In acetonitrile at 0℃; for 0.5h; Stage #3: With sulfuric acid at 20℃; for 1h; enantioselective reaction;
  • 41
  • [ 10340-91-7 ]
  • [ 196601-69-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: C65H83O4P / dichloromethane; water / 8 h / 20 °C 2.1: hydrogen; 5%-palladium/activated carbon / ethyl acetate / 4 h / 20 °C / 760.05 Torr 2.2: 0.5 h / 0 °C 2.3: 1 h / 20 °C
  • 42
  • (R)-2-azido-N-benzyl-3,3-dimethoxypropanamide [ No CAS ]
  • [ 196601-69-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: titanium tetrachloride / dichloromethane / 0.17 h / 0 °C / Inert atmosphere 1.2: 16.5 h / 0 °C / Inert atmosphere 2.1: trimethylphosphane / tetrahydrofuran; water / 3.08 h / 0 - 20 °C / Inert atmosphere
  • 43
  • (R)-2-azido-N-benzyl-3-methoxy propanamide [ No CAS ]
  • [ 196601-69-1 ]
YieldReaction ConditionsOperation in experiment
With trimethylphosphane In tetrahydrofuran; water at 0 - 20℃; for 3.08333h; Inert atmosphere;
  • 44
  • [ 19337-34-9 ]
  • [ 196601-69-1 ]
  • (R)-N-(1-(benzylamino)-3-methoxy-1-oxopropan-2-yl)butyramide [ No CAS ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran at 20℃; for 16h;
  • 45
  • C8(13)CH11NOS [ No CAS ]
  • [ 196601-69-1 ]
  • C14(13)CH22N2O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran at 20℃; for 16h;
  • 46
  • C24H24N2O2 [ No CAS ]
  • [ 196601-69-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: hydrogenchloride / dichloromethane; water / 20 °C 2: benzaldehyde; phosphoric acid; L-Tartaric acid / methanol / 50 °C / pH 6
  • 47
  • [ 262845-82-9 ]
  • [ 196601-69-1 ]
YieldReaction ConditionsOperation in experiment
72% With L-Tartaric acid; phosphoric acid; benzaldehyde In methanol at 50℃; 5 To the intermediate M4 obtained in Example 4, anhydrous methanol was added, 1 mL of benzaldehyde was added at room temperature, pH was adjusted to 6 with phosphoric acid, the temperature was raised to 50°C, and the methanol solution of L-tartaric acid was added dropwise. After the addition was completed, the reaction was kept warm. , Filtered and dried to obtain 32.2g of intermediate M5,
  • 48
  • O-(1-((N,4-dimethylphenyl)sulfonamido)vinyl) ethanethioate [ No CAS ]
  • [ 196601-69-1 ]
  • (R)-N-benzyl-2-ethanethioamido-3-methoxypropanamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
93% In dichloromethane at 20℃; for 0.333333h; Green chemistry;
  • 49
  • [ 64-19-7 ]
  • [ 196601-69-1 ]
  • [ 175481-36-4 ]
YieldReaction ConditionsOperation in experiment
at 20℃; Add INT3 (50g, 0.16mol) and dichloromethane (500mL) into the reaction flask, add 36wt% concentrated hydrochloric acid (82.2g, 0.8mol) to the reaction flask, react at room temperature for 12h until the reaction is complete, add water to the reaction solution 100mL, stir and let stand, separate liquids, keep the water phase, adjust pH=11-13 with 30wt% sodium hydroxide solution, extract the water phase with dichloromethane, combine the organic phases, then add the organic phase to the reaction flask, turn on stirring , and add acetic anhydride (16.6g, 0.16mol), react at room temperature for 1-2h to the completion of the reaction, the reaction solution is washed with purified water, saturated sodium bicarbonate and saturated NaCl respectively, and then the organic phase is concentrated to a large amount of solid and then added with n-hexane alkane (500 mL), stirred at room temperature for 2 h, filtered, and the filter cake was dried to obtain crude lacosamide (28.8 g, 71.0%).
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Reason: Free-salt

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[ 1706821-62-6 ]

4-Benzyl-N-methylmorpholine-3-carboxamide

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Chemical Structure| 1706818-30-5

[ 1706818-30-5 ]

4-Benzylmorpholine-3-carboxamide

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[ 433283-16-0 ]

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