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

HRID 1050862ノート

反応式

HRID 1050862 の反応式
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]

参加物

7

反応物 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

生成物 1

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

試薬・触媒・溶媒 2

HCID 9811564Bis(dibenzylideneacetone)palladium触媒HCID 312751,4-Dioxane溶媒

反応条件

温度
100 °C

実験手順

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+).

後処理

  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

出典と根拠

ORDレコード
ord-5f733dd8b6e44be9857992db83ab370b
出典データセット
uspto-grants-2016_07
特許番号
US09387202B2

反応ノート

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