Ethanol → Lenvatinib

HRID 869487Notes

Reaction equation

HRID 869487 reaction equation
[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[C:7]2[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=O)[O:25]C2C=CC=CC=2)=[C:19]([Cl:33])[CH:18]=1)(=[O:3])[NH2:2].[CH:34]1([NH2:37])[CH2:36][CH2:35]1.O.C(O)C>CN(C)C=O>[Cl:33][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[NH:23][C:24]([NH:37][CH:34]1[CH2:36][CH2:35]1)=[O:25])[O:16][C:7]1[C:6]2[C:11](=[CH:12][C:13]([O:14][CH3:15])=[C:4]([C:1]([NH2:2])=[O:3])[CH:5]=2)[N:10]=[CH:9][CH:8]=1

Participants

6

Reactant 4

HCID 702EthanolHCID 962WaterHCID 69828CyclopropylamineHCID 22936529(4-((6-(Aminocarbonyl)-7-methoxy-4-quinolinyl)oxy)-2-chlorophenyl)carbamic acid phenyl ester

Product 1

HCID 9823820Lenvatinib

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

Phenyl N-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate (17.5 g, 37.7 mmol) disclosed in WO 02/32872 was dissolved in N,N-dimethylformamide (350 mL), and then cyclopropylamine (6.53 mL, 94.25 mmol) was added to the reaction mixture under a nitrogen atmosphere, followed by stirring overnight at room temperature. To the mixture was added water (1.75 L), and the mixture was stirred. Precipitated crude crystals were collected by filtration, washed with water, and dried at 70° C. for 50 min. To the obtained crude crystals was added ethanol (300 mL), and then the mixture was heated under reflux for 30 min to dissolve, followed by stirring overnight to cool slowly down to room temperature. Precipitated crystals was collected by filtration and dried under vacuum, and then further dried at 70° C. for 8 hours to give the titled crystals (12.91 g; 80.2%).

Workup

  1. stirringthe mixture was stirred
  2. customPrecipitated crude crystals
  3. filtrationwere collected by filtration
  4. washwashed with water
  5. customdried at 70° C. for 50 min
  6. customTo the obtained crude crystals
  7. temperaturethe mixture was heated
  8. temperatureunder reflux for 30 min
  9. dissolutionto dissolve
  10. stirringby stirring overnight
  11. temperatureto cool slowly down to room temperature
  12. customPrecipitated crystals
  13. filtrationwas collected by filtration
  14. customdried under vacuum
  15. customfurther dried at 70° C. for 8 hours
  16. customto give the titled crystals (12.91 g; 80.2%)

Sources & evidence

ORD record
ord-bfd86a27b9ab4449b9779a39c18a30de
Source dataset
uspto-grants-2015_03
Patent number
US08969379B2

Reaction notes

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