Acetamide → HCID 71575876, compound

HRID 1411159Notes

Reaction equation

HRID 1411159 reaction equation
[Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32](Cl)[CH:31]=2)=[CH:4][C:5]([F:28])=[C:6]([NH:8][C:9]([C:11]2[C:12](=[O:27])[N:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:14]=[CH:15][C:16]=2[O:17][CH2:18][CH3:19])=[O:10])[CH:7]=1.[C:37]([NH2:40])(=[O:39])[CH3:38].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.[Cl-].[Na+].O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:37]([NH:40][C:32]1[CH:31]=[C:30]([O:29][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([NH:8][C:9]([C:11]3[C:12](=[O:27])[N:13]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][CH3:19])=[O:10])=[C:5]([F:28])[CH:4]=2)[CH:35]=[CH:34][N:33]=1)(=[O:39])[CH3:38]

Participants

8

Reactant 4

HCID 178AcetamideHCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 86703366HCID 86703366, compound

Product 1

HCID 71575876HCID 71575876, compoundYield 51.8%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
100 °C

Procedure

N-(5-chloro-4-((2-chloropyridin-4-yl)oxy)-2-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.05 g, 0.094 mmol) was combined with acetamide (8 mg, 0.14 mmol), Cs2CO3 (0.05 g, 0.14 mmol) and Xantphos (6 mg, 0.010 mmol) in dioxane (2 mL) and the mixture sparged with argon for several minutes. Pd2(dba)3 (5 mg, 0.005 mmol) was added and the mixture was sparged again with argon. The reaction vessel was sealed and heated at 100° C. overnight. The cooled reaction mixture was diluted with brine and extracted with EtOAc (2×). The organics were dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by silica gel chromatography (50-100% EtOAc/hexanes). The purified residue was treated with CH3CN:H2O (1:1, 2 mL), frozen and lyophilized to obtain N-(4-((2-acetamidopyridin-4-yl)oxy)-5-chloro-2-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (27 mg, 50.5% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.19 (s, 1H), 10.57 (s, 1H), 8.50 (d, J=7.9 Hz, 1H), 8.17 (d, J=5.7 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.61 (br s, 1H), 7.49 (m, 3H), 7.36 (t, J=8.7 Hz, 2H), 6.65 (dd, J=5.7, 2.4 Hz, 1H), 6.55 (d, J=7.9 Hz, 1H), 4.28 (q, J=7.0 Hz, 2H), 2.03 (s, 3H), 1.34 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 555.1 (M+H+).

Workup

  1. customthe mixture sparged with argon for several minutes
  2. customthe mixture was sparged again with argon
  3. customThe reaction vessel was sealed
  4. customThe cooled reaction mixture
  5. extractionextracted with EtOAc (2×)
  6. dry with materialThe organics were dried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe crude was purified by silica gel chromatography (50-100% EtOAc/hexanes)
  10. additionThe purified residue was treated with CH3CN:H2O (1:1, 2 mL)
  11. temperaturefrozen

Sources & evidence

ORD record
ord-6e74789c4e2940b4b0f79653cec56802
Source dataset
uspto-grants-2014_12
Patent number
US08921565B2

Reaction notes

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