4-Chloro-N-methylpicolinamide → Sorafenib

HRID 2094780Notes

Reaction equation

HRID 2094780 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].CC(C)([O-])C.[K+].Cl[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]([NH:38][CH3:39])=[O:37])[CH:31]=1>CN(C)C=O.C(OCC)(=O)C.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][C:30]3[CH:35]=[CH:34][N:33]=[C:32]([C:36]([NH:38][CH3:39])=[O:37])[CH:31]=3)=[CH:16][CH:17]=2)=[CH:4][C:3]=1[C:19]([F:20])([F:21])[F:22]

Participants

7

Reactant 3

HCID 14768144-Chloro-N-methylpicolinamideHCID 23665647Potassium tert-butoxideHCID 25221150N-[4-Chloro-3-(trifluoromethyl)phenyl]-N'-(4-hydroxyphenyl)urea

Product 1

HCID 216239SorafenibYield 64.9%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent2×

Procedure

1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea (35 g, 0.1060 mol) was dissolved in dry N,N-dimethyl formamide (100 ml) and potassium tert-butoxide (14.28 g, 0.1272 mol) was added in one lot at room temperature. The reaction mass was stirred at ambient temperature for 2-3 hours and 4-chloro-N-methyl picolinamide (18.09 g, 0.1060 mol) was added in one lot. The reaction mass was maintained at 60-70° C. for 2-3 hours and cooled to room temperature. It was then diluted with ethyl acetate and the organic layer was washed with water followed by 1N HCl and finally with brine. The organic layer was separated, dried over sodium sulfate and degassed to obtain solid. The obtained solid was stripped with ethyl acetate, finally slurried in acetonitrile (350 ml) at room temperature, filtered and vacuum dried to give 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide (sorafenib) (32 g).

Workup

  1. temperatureThe reaction mass was maintained at 60-70° C. for 2-3 hours
  2. temperaturecooled to room temperature
  3. washthe organic layer was washed with water
  4. customThe organic layer was separated
  5. dry with materialdried over sodium sulfate
  6. customdegassed
  7. customto obtain solid
  8. filtrationfiltered
  9. customvacuum dried

Sources & evidence

ORD record
ord-90822f1efc2a4e1ea5a4bc9302f27a57
Source dataset
uspto-grants-2013_05
Patent number
US08445687B2

Reaction notes

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