Dimethylformamide → Sorafenib

HRID 2094781Notes

Reaction equation

HRID 2094781 reaction equation
[CH3:1][NH:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH2:20])=[O:19])=[CH:13][CH:12]=2)[CH:7]=[CH:6][N:5]=1.N12CCCN=C1CCCCC2.[F:33][C:34]([F:44])([F:43])[C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][C:41]=1[Cl:42])N.CN(C)C=O>C(OCC)(=O)C>[Cl:42][C:41]1[CH:40]=[CH:39][C:37]([NH:20][C:18](=[O:19])[NH:17][C:14]2[CH:15]=[CH:16][C:11]([O:10][C:8]3[CH:7]=[CH:6][N:5]=[C:4]([C:3]([NH:2][CH3:1])=[O:21])[CH:9]=3)=[CH:12][CH:13]=2)=[CH:36][C:35]=1[C:34]([F:33])([F:43])[F:44]

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 675744-Chloro-3-(trifluoromethyl)anilineHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 25221151N-methyl-4-(4-ureidophenoxy)picolinamide

Product 1

HCID 216239SorafenibYield 78.9%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

N-methyl-4-(4-ureidophenoxy)picolinamide (50 g, 0.1746 mol), 1,8-diazabicyclo[5.4.0]undec-7-ene (33.95 ml, 0.2270 mol) and 3-trifluoromethyl-4-chloroaniline (34.2 g, 0.1746 mol) were mixed with N,N-dimethyl formamide (200 ml) (DMF) and the reaction mass was heated to reflux for 24 hours. It was then cooled to room temperature and quenched in water (600 ml). The quenched mass was extracted repeatedly with ethyl acetate and the combined ethyl acetate layer was then back washed with water to remove DMF traces. It was then dried over sodium sulfate and evaporated under vacuum to obtain solid. The solid thus obtained was then slurried in ethyl acetate (400 ml) at ambient temperature and filtered to give 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide (sorafenib base) (64 g).

Workup

  1. temperaturethe reaction mass was heated
  2. temperatureto reflux for 24 hours
  3. customquenched in water (600 ml)
  4. extractionThe quenched mass was extracted repeatedly with ethyl acetate
  5. washthe combined ethyl acetate layer was then back washed with water
  6. customto remove DMF traces
  7. dry with materialIt was then dried over sodium sulfate
  8. customevaporated under vacuum
  9. customto obtain solid
  10. customThe solid thus obtained
  11. filtrationfiltered

Sources & evidence

ORD record
ord-55e8b609ed9e49ffaaf0b5c7e29fecb3
Source dataset
uspto-grants-2013_05
Patent number
US08445687B2

Reaction notes

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