Potassium tert-butoxide → 4-(3-Fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridine-2-carboxamide

HRID 2066252Notes

Reaction equation

HRID 2066252 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=3[F:24])=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.CC(C)([O-:28])C.[K+].Cl[C:32]1[CH:37]=[CH:36][N:35]=[C:34]([CH2:38][NH-:39])[CH:33]=1>CN1CCCC1=O>[F:24][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][C:17]=1[NH:16][C:14]([C:11]1([C:9](=[O:10])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:13][CH2:12]1)=[O:15])[O:23][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]([NH2:39])=[O:28])[CH:33]=1

Participants

5

Reactant 3

HCID 23665647Potassium tert-butoxideHCID 59596967N-(4-Fluorophenyl)-N'-(2-fluoro-4-hydroxyphenyl)cyclopropane-1,1-dicarboxamideHCID 866258584-Chloropicolylamide

Product 1

HCID 595970164-(3-Fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridine-2-carboxamideYield 29%

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Procedure

N-(4-Fluorophenyl)-N′-(2-fluoro-4-hydroxyphenyl)cyclopropane-1,1-dicarboxamide (665 mg) was dissolved in N-methylpyrrolidone (10 ml) under a nitrogen atmosphere, and potassium tert-butoxide (247 mg) was added at room temperature, followed by stirring for 1.5 hr. After 4-chloropicolylamide (313 mg) was added, the reaction mixture was stirred under a nitrogen atmosphere at 110° C. overnight, then at 120° C. for 8 hr. The reaction mixture was allowed to cool down to room temperature. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (twice) and brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=1:2, 1:3, then 1:4). Fractions containing the target compound were concentrated under reduced pressure. After ethyl acetate (3 ml)-heptane (6 ml) was added, crystals were allowed to precipitate under sonication. The solvent was removed and the crystals were dried under reduced pressure to provide the titled compound as pale brown crystals (261 mg, 29%).

Workup

  1. stirringthe reaction mixture was stirred under a nitrogen atmosphere at 110° C. overnight
  2. waitat 120° C. for 8 hr
  3. customThe reaction mixture was partitioned between ethyl acetate and water
  4. washThe organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (twice) and brine
  5. dry with materialdried over anhydrous sodium sulfate
  6. concentrationThe solvent was concentrated under reduced pressure
  7. customthe residue was purified by silica gel column chromatography (eluent
  8. additionFractions containing the target compound
  9. concentrationwere concentrated under reduced pressure
  10. additionAfter ethyl acetate (3 ml)-heptane (6 ml) was added
  11. customto precipitate under sonication
  12. customThe solvent was removed
  13. customthe crystals were dried under reduced pressure

Sources & evidence

ORD record
ord-f94915b34d2c413ab734adf5a37aaa00
Source dataset
uspto-grants-2012_10
Patent number
US08288538B2

Reaction notes

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