Structure of 1253790-58-7
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CAS No. : | 1253790-58-7 |
Formula : | C15H22N2O4 |
M.W : | 294.35 |
SMILES Code : | O=C(OC(C)(C)C)N[C@H](CO)C(NCC1=CC=CC=C1)=O |
MDL No. : | MFCD17011844 |
InChI Key : | CTFYHNRRPGOYJS-GFCCVEGCSA-N |
Pubchem ID : | 46223140 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319 |
Precautionary Statements: | P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.28% | With tetrabutylammomium bromide; sodium hydroxide; In water; toluene; at 0 - 30℃; for 1.5h; | Put toluene at room temperature (4.8L) with Lacosamide stage II product (1kg), cooled to 0 °C, put sodium hydroxide solution 1 (0.54kg), tetrabutylammonium bromide (0.186 kg) with dimethyl sulfate (0.86 kg), heated to 30 °C, stir for 90 minutes. Extracted with toluene, put 5percent sodium bicarbonate solution, separate the organic phase. Put cyclohexane, stirred for 10 minutes and concentrated at 50 °C under reduced pressure for 2 hours. Drying to obtain lacosamide stage III. Yield of about 96.28percent. |
75.8% | With sodium hydroxide;tetra(n-butyl)ammonium hydrogensulfate; In dichloromethane; water; at 4 - 25℃;Inert atmosphere; | 2.(R)-boc-2-amino-N-benzyl-3-methoxy-propionamide (IV)In a 4 L flask with overhead stirrer, thermometer, dropping funnel and under nitrogen were combined 120 g (R)-boc-2-amino-N-benzyl-3-hydroxy-propionamide (III) (0.407 mol) and 1 kg dichloromethane.The reaction was cooled on ice to 4-8°C and 6.9 g tetrabutylammonium bisulfate (6.8 mmol) and 285 g of 20percent sodium hydroxide in water (0.475 mol) added.To the reaction was then added 154 g (1.22 mol) dimethyl sulfate and the reaction stirred at 4-8 °C for 4 hours and overnight at 20-25 °C.A sample showed greater than 98percent methylation of the starting (R)-boc-2-amino-N-benzyl-3-hydroxy-propionamide.The reaction was quenched by additing 330 g of 25percent ammonium hydroxide solution in water plus a further 330 g water and stirred for 2 hours.The phases were then separated and the aqueous phase extracted with 340 g dichloromethane.The combined dichloromethane phases were washed with 450 ml water, then the dichloromethane was exchanged for tert-butyl methyl ether (MTBE) and the product crystallised from 345 ml MTBE at 4 °C overnight. The crystals were filtered and washed 2 times with 45 ml MTBE and dried to yield 95.3 g (75.8percent yield), HPLC purity = 98.6percent, ee >99percent ,1H NMR conforms. |
75.8% | 2. (R)-boc-2-amino-N-benzyl-3-methoxy-propionamide (IV)In a 4 L flask with overhead stirrer, thermometer, dropping funnel and under nitrogen were combined 120 g (R)-boc-2-amino-N-benzyl-3-hydroxy-propionamide (III) (0.407 mol) and 1 kg dichloromethane. The reaction was cooled on ice to 4-8° C. and 6.9 g tetrabutylammonium bisulfate (6.8 mmol) and 285 g of 20percent sodium hydroxide in water (0.475 mol) added. To the reaction was then added 154 g (1.22 mol) dimethyl sulfate and the reaction stirred at 4-8° C. for 4 hours and overnight at 20-25° C. A sample showed greater than 98percent methylation of the starting (R)-boc-2-amino-N-benzyl-3-hydroxy-propionamide. The reaction was quenched by additing 330 g of 25percent ammonium hydroxide solution in water plus a further 330 g water and stirred for 2 hours. The phases were then separated and the aqueous phase extracted with 340 g dichloromethane. The combined dichloromethane phases were washed with 450 ml water, then the dichloromethane was exchanged for tert-butyl methyl ether (MTBE) and the product crystallised from 345 ml MTBE at 4° C. overnight. The crystals were filtered and washed 2 times with 45 ml MTBE and dried to yield 95.3 g (75.8percent yield), HPLC purity=98.6percent, ee >99percent, 1H NMR conforms. |
With tetrabutylammomium bromide; sodium hydroxide; In water; toluene; at 10℃; for 2h; | Intermediate 5: Preparation of tert-butyl [(2R)-1-(benzylamino)-3-methoxy-1-oxopropan-2-yl]carbamateTo a stirred solution of 3.2 g (0.01 mol) of Intermediate 4 in 50 mL of toluene was added 0.61 g of tetrabutylammonium bromide and 5 ml of water. The resulting mixture was cooled to 10° C. and a solution of 2.4 g of sodium hydroxide in 2.5 ml of water was added dropwise maintaining the temperature below 10° C. Then, 5.54 g of dimethylsulfate was added dropwise maintaining the temperature below 10° C. After stirring at 10° C. for 2 hours, water (80 mL) was added and the reaction stirred at room temperature overnight. The layers were separated and the aqueous layer was washed twice with dichloromethane (50 mL). The combined organic phase was washed with sodium bicarbonate solution (2.x.30 mL) and brine. The solvent was removed under vacuum yielding 3.36 g of a pale red-oil. The oil was not purified and used directly in the following step. | |
Step 2:Production of (R)-N-benzyl-2-N-Boc-amino-3-methoxypropionamide.; (R)-N-Benzyl-2-N-Boc amino-3-hydroxy propionamide solution prepared as per the method b was cooled to < 5°C and potassium hydroxide (17.6 g, 0.3136 mol) was added at <5°C. The resulting suspension was aged for 5-10 min at <5°C and dimethyl sulfate (29.6 g, 0.2346 mol) was added at <5°C in 10- 15 min. The resulting mixture was aged for 3-5 h at <5°C. Water (80 ml) was added to the suspension and separated the phases. The organic layer was washed with a solution of citric acid (20.0 g) in DM water (80 ml) to produce (R)-N-benzyl-2-N-Boc- amino-3-methoxypropionamide solution in methylene chloride with HPLC purity (90percent), chiral 1 purity (98percent). The purity of the crude compound is optionally improved by crystallization from a mixture of hexane and ethyl acetate. | ||
With sodium hydroxide;tetrabutylammomium bromide; In dichloromethane; water; at 5 - 20℃; for 2h; | To the above solution of (i?)-N-benzyl-2-N-Boc-amino-3-hydroxypropionamide in dichloromethane was added 50percent w/w aqueous solution of sodium hydroxide 250 ml (4.75 mole) and tetrabutylammonium bromide 12.0 g (0.036 mole). Cooled to 5° C, added dimethyl sulfate 389.5 g (3.09 mole) and stirred at ambient temperature for 2 hrs. he aqueous layer was separated, and the organic layer was washed with water to obtain a solution of (j?)-N-benzyl-2-N-Boc-amino-3-methoxypropionamide in dichoromethane | |
With tetrabutylammomium bromide; sodium hydroxide; In water; toluene; at 2 - 27℃; | Reaction mass of Stage II (190 g), toluene (950 ml), NaOH (71 g in 380ml of process water) (~415ml) and tetrabutyl ammonium bromide (35.36 g) were added at 27±3°C. Cooled the reaction mass to 2±3°C and the solution was stirred for 5-10 min. at 2±3°C and dimethyl sulfate (162.8 g) was added at 2±3°C followed by stirring for 5-10 min. at 2±3°C. Raised the temperature of reaction mass to 27±3°C and then it was stirred for 90 min. at the same temperature. The layers were separated. The organic layer was collected. The aqueous layer was extracted with toluene (190 ml), stirred and allowed to settle. The combined organic layers were washed with 5percent w/v sodium bicarbonate solution (47.5 g in 950 ml). The organic layer was collected and distilled out toluene completely under vacuum at below 56°C to obtained residue. Cyclohexane (190 ml) was added to residue at below 56°C and distilled out cyclohexane completely under vacuum at below 56°C. Degas the residue for 1-2 hr under vacuum (720 mm/Hg) at below 56°C. Cyclohexane (380 ml) was added to residue at below 56°C. Cooled the reaction mass to 27±3°C and then it was stirred for 2-3 hr. at the same temperature. Solid was filtered and washed with cyclohexane (190 ml) at 27±3°C. The solid was dried under vacuum at 47±3°C. | |
With tetrabutylammomium bromide; sodium hydroxide; In dichloromethane; at 5 - 20℃; for 2h; | To the above solution of (R)-N-benzyl-2-N-Boc-amino-3-hydroxypropionamide in dichloromethane was added 50percent w/w aqueous solution of sodium hydroxide 250 ml (4.75 mole) and tetrabutylammonium bromide 12.0 g (0.036 mole). Cooled to 5° C., added dimethyl sulfate 389.5 g (3.09 mole) and stirred at ambient temperature for 2 hrs. The aqueous layer was separated, and the organic layer was washed with water to obtain a solution of (R)-N-benzyl-2-N-Boc-amino-3-methoxypropionamide in dichoromethane. | |
Step 2 Production of (R)-N-benzyl-2-N-Boc-amino-3-methoxypropionamide (R)-N-Benzyl-2-N-Boc amino-3-hydroxy propionamide solution prepared as per the method b was cooled to <5° C. and potassium hydroxide (17.6 g, 0.3136 mol) was added at <5° C. The resulting suspension was aged for 5-10 min at <5° C. and dimethyl sulfate (29.6 g, 0.2346 mol) was added at <5° C. in 10-15 min. The resulting mixture was aged for 3-5 h at <5° C. Water (80 ml) was added to the suspension and separated the phases. The organic layer was washed with a solution of citric acid (20.0 g) in DM water (80 ml) to produce (R)-N-benzyl-2-N-Boc-amino-3-methoxypropionamide solution in methylene chloride with HPLC purity (90percent), chiral purity (98percent). | ||
With potassium hydroxide; In dichloromethane; at 10 - 20℃; | A solution of tert-butyl [(2R)-l-(benzylamino)-3-hydroxy-l-oxopropan-2-yl]carbamate (300 g, 1.019 mol) in methylene chloride (1500 ml) was cooled to 10-15 °C and potassium hydroxide (102.7 g, 1.834 mol) was added maintaining the temperature below 15 °C. Dimethyl sulfate (218.38 g, 1.733 mol) was added below 15 °C in 10-15 min. The resulting mixture was stirred for 3-5 h at room temperature and water (1200 ml) was added. The layers were separated and the organic layer was evaporated under reduced pressure to obtain tert-butyl [(2i?)-l-(benzylamino)-3-methoxy-l-oxopropan-2- yl]carbamate in oil form having HPLC purity more than 90percent. This material was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With tetrabutylammomium bromide; potassium hydroxide; In toluene; at -1 - 2℃; | Toluene (820 mL), Intermediate III (50 g), methyl p-toluenesulfonate (63.5 g),Tetrabutylammonium bromide (5.4 g) was added and the mixture was cooled with stirring to -1 to 2 ° C. Potassium hydroxide aqueous solution (40 g / 34 mL) was added at -1 to 2 ° C, and the addition was completed in about 5 minutes. The addition was complete, continue to control the temperature at -1 ~ 2 reaction 4 ~ 4.5 hours (TLC detection or HPLC control) to stop the reaction. After completion of the reaction, water (400 mL) was added to separate the layers. Organic layer followed by 5percent phosphoric acid, saturated sodium bicarbonate, water each200mL wash. Decompression 40 ~ 45 ° C The solvent was evaporated to give an oil, the reaction was used directly for the next step. HPLC purity 95percent, chiral Purity 99.1percent. |
60.97g | With tetrabutylammomium bromide; potassium hydroxide; In water; toluene; at 20℃; for 3h; | Toluene (330 mL) was added sequentially to the 1 L reaction flask,The compound of formula II (20.00 g, 68 mmol)P-toluenesulfonic acid methyl ester (63.50 g, 340 mmol),Tetrabutylammonium bromide (2.63 g, 8.16 mmol),Stir evenly,An aqueous solution of potassium hydroxide (16.00 g of potassium hydroxide + 16 mL of water) was added at room temperature,Plus complete, room temperature reaction 3 hours.Reaction completed, adding water (160mL), stirring 5min, standing stratification, liquid separation,Organic layer followed by 5percent phosphoric acid(80 mL), water (160 mL x 2), and the organic layer was concentrated at 55 ° C under reduced pressure. The solvent was evaporated to give 60.97 g of an oil.The product of this example was the same as in Example 1 by isolation and identification. |
38.5 g | With tetrabutylammomium bromide; sodium hydroxide; In water; at 20℃; for 3h; | To a 1L reaction flask were sequentially added toluene (330 mL), Compound II (20.00 g, 68 mmol), methyl p-toluenesulfonate (38.10 g, 204 mmol), tetrabutylammonium bromide (2.63 g, 8.16 mmol), Stir well, add aqueous sodium hydroxide solution (16.00g of sodium hydroxide + 16mL of water) at room temperature, complete the addition, and react at room temperature for 3 hours. After the reaction is complete, add water (160 mL), stir for 5 min, stand for layering, separate the liquid, and use 5percent phosphoric acid in order for the organic layer.(80 mL) and water (160 mL×2) were washed. The organic layer was concentrated under reduced pressure at 55° C., and the solvent was evaporated to give 38.5 g of an oil. |
38.5 g | With tetrabutylammomium bromide; sodium hydroxide; In water; toluene; at 20℃; for 3h; | Toluene (330 mL) was added sequentially to a 1L reaction flask,Compound II (20.00 g, 68 mmol),Methyl p-toluenesulfonate (38.10 g, 204 mmol),Tetrabutylammonium bromide (2.63 g, 8.16 mmol),Stir well,An aqueous solution of sodium hydroxide (16.00 g of sodium hydroxide + 16 mL of water) was added at room temperature.After the addition, the reaction was carried out at room temperature for 3 hours.After the reaction is complete, add water (160 mL) and stir for 5 min.Static stratification, liquid separation,The organic layer was successively washed with 5percent phosphoric acid (80 mL) and water (160 mL×2), and the organic layer was concentrated under reduced pressure at 55° C.After the solvent was distilled off, 38.5 g of an oil was obtained. |
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