4-Chloro-3-(trifluoromethyl)aniline → Sorafenib

HRID 2094785Notes

Reaction equation

HRID 2094785 reaction equation
[CH3:1][NH:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N:17](Cl)[C:18](=[O:23])C(Cl)(Cl)Cl)=[CH:13][CH:12]=2)[CH:7]=[CH:6][N:5]=1.N12CCCN=C1CCCCC2.[F:37][C:38]([F:48])([F:47])[C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][C:45]=1[Cl:46])[NH2:42]>CN(C)C=O.C(OCC)(=O)C>[Cl:46][C:45]1[CH:44]=[CH:43][C:41]([NH:42][C:18](=[O:23])[NH:17][C:14]2[CH:13]=[CH:12][C:11]([O:10][C:8]3[CH:7]=[CH:6][N:5]=[C:4]([C:3]([NH:2][CH3:1])=[O:25])[CH:9]=3)=[CH:16][CH:15]=2)=[CH:40][C:39]=1[C:38]([F:37])([F:47])[F:48]

Participants

6

Reactant 3

HCID 675744-Chloro-3-(trifluoromethyl)anilineHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 86648444HCID 86648444, compound

Product 1

HCID 216239SorafenibYield 66.8%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
110 °C

Procedure

N-methyl-4-(4-(2,2,2-trichlorochloroacetamido)phenoxy)picolinamide (25 g, 0.0644 mol) was dissolved in N,N-dimethyl formamide (75 ml). 1,8-Diazabicyclo[5.4.0]undec-7-ene (11.35 ml, 0.0805 mol) and 3-trifluoromethyl-4-chloroaniline (12.60 g, 0.0644 mol) were added in one lot. The reaction mass was then heated to 110° C. for 8-9 hours, cooled to room temperature and quenched in water (250 ml). The quenched mass was extracted repeatedly with ethyl acetate and the combined ethyl acetate layer was back washed with water to remove DMF traces. It was dried over sodium sulfate and evaporated under vacuum to obtain solid. The obtained solid was slurried in ethyl acetate (350 ml) at ambient temperature and filtered to give 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide (sorafenib base) (20 g).

Workup

  1. temperaturecooled to room temperature
  2. customquenched in water (250 ml)
  3. extractionThe quenched mass was extracted repeatedly with ethyl acetate
  4. washthe combined ethyl acetate layer was back washed with water
  5. customto remove DMF traces
  6. dry with materialIt was dried over sodium sulfate
  7. customevaporated under vacuum
  8. customto obtain solid
  9. filtrationfiltered

Sources & evidence

ORD record
ord-bf41af48d7f44d92958f4ef25f18e89e
Source dataset
uspto-grants-2013_05
Patent number
US08445687B2

Reaction notes

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