Acetamide → HCID 54576083, compound

HRID 476369Notes

Reaction equation

HRID 476369 reaction equation
Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3([C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])[CH2:21][CH2:20]3)=[O:18])=[C:11]([F:31])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:32]([NH2:35])(=[O:34])[CH3:33].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.ClCCl>[C:32]([NH:35][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3([C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])[CH2:21][CH2:20]3)=[O:18])=[C:11]([F:31])[CH:10]=2)[CH:5]=[CH:4][N:3]=1)(=[O:34])[CH3:33]

Participants

8

Reactant 4

HCID 178AcetamideHCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 86662873HCID 86662873, compound

Product 1

HCID 54576083HCID 54576083, compoundYield 58.1%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

N-(4-(2-chloropyridin-4-yloxy)-2,5-difluorophenyl)-N′-phenylcyclopropane-1,1-dicarboxamide (0.162 g, 0.365 mmol), acetamide (0.108 g, 1.825 mmol), cesium carbonate (0.178 g, 0.548 mmol), and xantphos (0.021 g, 0.036 mmol) were combined in dry dioxane (2.61 mL) and argon was bubbled through the mixture for 5 minutes. Palladium acetate (6.15 mg, 0.027 mmol) was added, and argon was bubbled through the mixture for an additional 5 minutes. The reaction flask was fitted with a reflux condenser and a balloon of argon and the mixture was heated at 100° C. for 20 hours. The reaction mixture was cooled to room temperature and partitioned between a 4:1 mixture of ethyl acetate and THF (50 mL) and water (50 mL). The aqueous layer was removed and the organic layer was washed with additional water (50 mL) and brine (50 mL). The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to yield a light peach-colored film. Dichloromethane (10 mL) was added and after a few minutes solid began to precipitate. Sonication was used to precipitate out more solid. After sitting for 30 minutes the bright white solid was collected by suction filtration and washed with additional dichloromethane to give N-(4-(2-acetamidopyridin-4-yloxy)-2,5-difluorophenyl)-N′-phenylcyclopropane-1,1-dicarboxamide (0.099 g, 58% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.98 (s, 1H), 10.59 (s, 1H), 9.78 (s, 1H), 8.19 (d, 1H), 8.07 (dd, 1H), 7.65 (d, 1H), 7.55 (m, 3H), 7.32 (m, 2H), 7.09 (t, 1H), 6.71 (dd, 1H), 2.02 (s, 3H), 1.63 (m, 2H), 1.57 (m, 2H); MS (ESI) m/z: 467.2 (M+H+).

Workup

  1. customargon was bubbled through the mixture for 5 minutes
  2. customargon was bubbled through the mixture for an additional 5 minutes
  3. customThe reaction flask was fitted with a reflux condenser
  4. temperatureThe reaction mixture was cooled to room temperature
  5. custompartitioned between a 4:1 mixture of ethyl acetate and THF (50 mL) and water (50 mL)
  6. customThe aqueous layer was removed
  7. washthe organic layer was washed with additional water (50 mL) and brine (50 mL)
  8. dry with materialThe organic layer was dried over magnesium sulfate
  9. customevaporated under reduced pressure
  10. customto yield a light peach-colored film
  11. customto precipitate
  12. customSonication
  13. customto precipitate out more solid
  14. filtrationthe bright white solid was collected by suction filtration
  15. washwashed with additional dichloromethane

Sources & evidence

ORD record
ord-792925bfa85c4ddbaa324cea74b815fe
Source dataset
uspto-grants-2014_01
Patent number
US08637672B2

Reaction notes

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