Formic Acid → Eslicarbazepine acetate

HRID 872939Notes

Reaction equation

HRID 872939 reaction equation
[CH:1]1[CH:2]=[CH:3][C:4]2[N:16]([C:17]([NH2:19])=[O:18])[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:8](=[O:9])[CH2:7][C:5]=2[CH:6]=1.[C:20](OCC)(=[O:22])[CH3:21].O.C(O)=O>CN(C)C=O>[CH3:21][C:20]([O:9][C@@H:8]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[N:16]([C:17]([NH2:19])=[O:18])[C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=2[CH2:7]1)=[O:22]

Participants

6

Reactant 4

HCID 284Formic Acid2×HCID 962WaterHCID 8857Ethyl AcetateHCID 34312Oxcarbazepine

Product 1

HCID 179344Eslicarbazepine acetate

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

In a 250 ml flask with overhead stirrer, reflux condenser and under nitrogen were combined: 16 g oxcarbazepine (63 mmol, 1 mol eq), 120 ml of ethyl acetate, 35 g IRA-67 tertiary ion exchange resin (SigmaAldrich, cat 476633), 10 ml water and 4.4 g formic acid (96 mmol, 1.5 mol eq). 35 mg RuCl [(S,S)-Ts-DPEN](p-cymene) (SigmaAldrich #703915) was dissolved in 10 ml dimethylformamide and added to the reactor. The reaction was heated in an oil bath to reflux. After 29 hours, without any further formic acid addition, the conversion had reached 98,4%. Product was isolated by filtering off the resin and washing with a 20 ml ethyl acetate. The combined organic phases were then washed with 10 ml water which was separated off. After cooling in the fridge, the product was filtered off and washed twice with 15 ml ethyl acetate. The isolated product had an ee of 98%. After acetylation and crystallisation using a similar method to that described in Example 3, eslicarbazepine acetate was isolated with an ee of 99.8% and product purity of 99.9% (HPLC area %, 210 nm).

Workup

  1. temperatureIn a 250 ml flask with overhead stirrer, reflux condenser
  2. additionadded to the reactor
  3. temperatureThe reaction was heated in an oil bath
  4. temperatureto reflux
  5. customProduct was isolated
  6. filtrationby filtering off the resin
  7. washwashing with a 20 ml ethyl acetate
  8. washThe combined organic phases were then washed with 10 ml water which
  9. customwas separated off
  10. temperatureAfter cooling in the fridge
  11. filtrationthe product was filtered off
  12. washwashed twice with 15 ml ethyl acetate
  13. customAfter acetylation and crystallisation

Sources & evidence

ORD record
ord-e6852625763d4bbf8c1af70a29f81eeb
Source dataset
uspto-grants-2015_03
Patent number
US08975396B2

Reaction notes

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