Benzylamine → Lacosamide

HRID 410135Notes

Reaction equation

HRID 410135 reaction equation
[C:1]([NH:4][C@@H:5]([C:9]([OH:11])=O)[CH2:6][O:7][CH3:8])(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(OCC)(=O)C>[CH3:2][C:1]([NH:4][C@@H:5]([C:9]([NH:34][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:11])[CH2:6][O:7][CH3:8])=[O:3]

Participants

6

Reactant 4

HCID 7504BenzylamineHCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 10558933(R)-2-Acetylamino-3-methoxy-propionic acid

Product 1

HCID 219078Lacosamide

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-20 °C

Procedure

Into a 2 L, four-necked RB flask was charged 1250 ml of ethyl acetate and 25 g of N-acetyl-O-methyl-D-serine under nitrogen atmosphere. The reaction mass was cooled to −20° C. and added 16.5 g of N-methylmorpholine. Isobutyl chloroformate (22.3 g) was slowly added to the reaction mass. After stirring for 30 min benzylamine (17.5 g) was slowly added to the reaction mass and stirred for 30 min. Temperature of the reaction mass was raised to 25-30° C. and stirred for 1 h. Reaction mass was quenched with 100 ml of 1N HCl and transferred into a separating funnel. Organic layer was washed with brine and dried over sodium sulphate. Solvent was partially distilled of from the mass under vacuum. The residue was kept under stirring and filtered the solid. The wet solid was recrystallized from ethyl acetate to get 35 g of pharma grade lacosamide. Chiral HPLC purity is >99.9% and the related impurities are <0.5%.

Workup

  1. additionwas slowly added to the reaction mass
  2. temperatureTemperature of the reaction mass was raised to 25-30° C.
  3. stirringstirred for 1 h
  4. customReaction mass
  5. customwas quenched with 100 ml of 1N HCl
  6. customtransferred into a separating funnel
  7. washOrganic layer was washed with brine
  8. dry with materialdried over sodium sulphate
  9. distillationSolvent was partially distilled of from the mass under vacuum
  10. stirringunder stirring
  11. filtrationfiltered the solid
  12. customThe wet solid was recrystallized from ethyl acetate

Sources & evidence

ORD record
ord-d7b053f61420466f8ad8848373dcc427
Source dataset
uspto-grants-2014_06
Patent number
US08759582B2

Reaction notes

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