Acetamide → N-(4-((2-acetamidopyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

HRID 1050862Notes

Reaction equation

HRID 1050862 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:20](=[O:35])[N:21]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH:22]=[CH:23][C:24]=3[O:25][CH2:26][CH3:27])=[O:18])=[C:11]([F:36])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:37]([NH2:40])(=[O:39])[CH3:38].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.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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: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:20](=[O:35])[N:21]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[CH:22]=[CH:23][C:24]=3[O:25][CH2:26][CH3:27])=[O:18])=[C:11]([F:36])[CH:10]=2)[CH:5]=[CH:4][N:3]=1)(=[O:39])[CH3:38]

Participants

7

Reactant 4

HCID 178AcetamideHCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 86703361N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

Product 1

HCID 71566461N-(4-((2-acetamidopyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamideYield 44%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (36 g, 69.9 mmol), acetamide (12.4 g, 209 mmol), Xantphos (4 g, 6.9 mmol), Cs2CO3 (45.5 g, 140 mmol) and Pd2(dba)3 (3.84 g, 4.2 mmol) in dioxane (500 mL) was heated at 100° C. under nitrogen for 2 h. The reaction mixture was cooled to RT, filtered to remove inorganic salts, and concentrated under vacuum. The residue was treated with water (300 mL) and extracted with EtOAc (3×400 mL). The combined organics were washed with brine, dried over Na2SO4 and concentrated dryness. The residue was purified by silica gel chromatography to afford N-(4-((2-acetamidopyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (15 g, 44% yield). 1H NMR (400 MHz, DMSO-d6): 11.23 (s, 1 H), 10.60 (s, 1 H), 8.34 (dd, J=12.8, 7.2 Hz, 1 H), 8.20 (d, J=5.6 Hz, 1 H), 7.94 (d, J=8.0 Hz, 1 H), 7.68 (s, 1 H), 7.56-7.51 (m, 3 H), 7.40-7.36 (m, 2 H), 6.73 (dd, J=5.6, 2.4 Hz, 1 H), 6.56 (d, J=8.0 Hz, 1 H), 4.30 (q, J=6.8 Hz, 2 H), 2.05 (s, 3 H), 1.35 (t, J=6.8 Hz, 3 H); MS (ESI) m/z: 539.1 (M+H+).

Workup

  1. temperatureThe reaction mixture was cooled to RT
  2. filtrationfiltered
  3. customto remove inorganic salts
  4. concentrationconcentrated under vacuum
  5. additionThe residue was treated with water (300 mL)
  6. extractionextracted with EtOAc (3×400 mL)
  7. washThe combined organics were washed with brine
  8. dry with materialdried over Na2SO4
  9. concentrationconcentrated dryness
  10. customThe residue was purified by silica gel chromatography

Sources & evidence

ORD record
ord-5f733dd8b6e44be9857992db83ab370b
Source dataset
uspto-grants-2016_07
Patent number
US09387202B2

Reaction notes

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