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Chemical Structure| 196601-69-1 Chemical Structure| 196601-69-1
Chemical Structure| 196601-69-1

(R)-2-Amino-N-benzyl-3-methoxypropanamide

CAS No.: 196601-69-1

Synonyms: DP-I; (R)-Amino-N-benzyl-3-methoxypropionamide

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Cat. No.: A215570 Purity: 95%

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Product Details of [ 196601-69-1 ]

CAS No. :196601-69-1
Formula : C11H16N2O2
M.W : 208.25
SMILES Code : O=C(NCC1=CC=CC=C1)[C@H](N)COC
Synonyms :
DP-I; (R)-Amino-N-benzyl-3-methoxypropionamide
MDL No. :MFCD14708219
InChI Key :WPLANNRKFDHEKD-SNVBAGLBSA-N
Pubchem ID :10104501

Safety of [ 196601-69-1 ]

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

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   1~1

  • 1
  • [ 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.

 

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