Acetamide → HCID 54576082, compound

HRID 476368Notes

Reaction equation

HRID 476368 reaction equation
[Cl:1][C:2]1[C:3]([O:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28](Cl)[CH:27]=2)=[CH:4][C:5]([F:24])=[C:6]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])[CH:7]=1.[C:33]([NH2:36])(=[O:35])[CH3:34].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CO>[C:33]([NH:36][C:28]1[CH:27]=[C:26]([O:25][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([NH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=4)=[O:15])[CH2:12][CH2:13]3)=[O:10])=[C:5]([F:24])[CH:4]=2)[CH:31]=[CH:30][N:29]=1)(=[O:35])[CH3:34]

Participants

8

Reactant 4

HCID 178AcetamideHCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 86662872HCID 86662872, compound

Product 1

HCID 54576082HCID 54576082, compoundYield 47.8%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 887MethanolSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

N-(5-cloro-4-(2-chloropyridin-4-yloxy)-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (0.200 g, 0.418 mmol), acetamide (0.124 g, 2.091 mmol), cesium carbonate (0.136 g, 0.418 mmol), and xantphos (0.017 g, 0.029 mmol) were dissolved in dry dioxane (3 mL) in a 25 mL round bottom flask. Argon was bubbled through the reaction mixture for 5 minutes, and then palladium acetate (4.69 mg, 0.021 mmol) was added. The mixture was again degassed for five minutes, and then the reaction flask was fitted with a reflux condenser. The system was flushed with argon and then heated at 100° C. under a balloon of argon for 3 hours. The reaction mixture was cooled to room temperature and diluted with water (30 mL) and a 4:1 mixture of ethyl acetate and THF (150 mL). The layers were separated, and the aqueous layer was washed with additional ethyl acetate/THF solution. The organic layers were combined and concentrated to yield a sticky orange oil. Upon addition of methanol (3 mL) a fine cream-colored precipitate formed, which was collected by suction filtration and washed with a small portion of dichloromethane to yield N-(4-(2-acetamidopyridin-4-yloxy)-5-chloro-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (0.100 g, 47.7% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.91 (s, 1H), 10.58 (s, 1H), 9.83 (s, 1H), 8.23 (d, 1H), 8.18 (d, 1H), 7.58 (m, 4H), 7.15 (m, 2H), 6.65 (dd, 1H), 2.02 (s, 3H), 1.61 (m, 2H), 1.56 (m, 2H); MS (ESI) m/z: 501.1 (M+H+).

Workup

  1. customArgon was bubbled through the reaction mixture for 5 minutes
  2. customThe mixture was again degassed for five minutes
  3. customthe reaction flask was fitted with a reflux condenser
  4. customThe system was flushed with argon
  5. temperatureThe reaction mixture was cooled to room temperature
  6. additiondiluted with water (30 mL)
  7. additiona 4:1 mixture of ethyl acetate and THF (150 mL)
  8. customThe layers were separated
  9. washthe aqueous layer was washed with additional ethyl acetate/THF solution
  10. concentrationconcentrated
  11. customto yield a sticky orange oil
  12. customformed
  13. filtrationwhich was collected by suction filtration
  14. washwashed with a small portion of dichloromethane

Sources & evidence

ORD record
ord-95955eb3fc1b4a3dbf99526a942888ff
Source dataset
uspto-grants-2014_01
Patent number
US08637672B2

Reaction notes

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