Cesium carbonate → N-(2,5-difluoro-4-((2-pivalamidopyridin-4-yl)oxy)phenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

HRID 1050865ノート

反応式

HRID 1050865 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]([NH2:43])(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39].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]>[F:36][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[CH:7]=2)[C:14]([F:15])=[CH:13][C:12]=1[NH:16][C:17]([C:19]1[C:20](=[O:35])[N:21]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH3:27])=[O:18]

参加物

7

反応物 4

HCID 10796Cesium carbonateHCID 12957TrimethylacetamideHCID 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 71575772N-(2,5-difluoro-4-((2-pivalamidopyridin-4-yl)oxy)phenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide収率 29.7%

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

N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.15 g, 0.29 mmol, see: Example 1) was combined with pivalamide (0.12 g, 1.16 mmol), Xantphos (0.02 g, 0.033 mmol), and Cs2CO3 (0.14 g, 0.44 mmol) in dioxane (5 mL). The mixture was sparged with argon for several min, treated with Pd2(dba)3 (0.015 g, 0.016 mmol), and heated at 100° C. overnight. The mixture was cooled to RT and filtered, washing with dioxane. The filtrate was concentrated to dryness and the residue was purified by reverse-phase chromatography [10%-45% CH3CN/H2O with 0.1% TFA]. The pure fractions were combined and co-evaporated with MeOH. The aqueous layer was neutralized with NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain N-(2,5-difluoro-4-((2-pivalamidopyridin-4-yl)oxy)phenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (50 mg, 29.6% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.23 (s, 1 H), 9.89 (s, 1 H), 8.34 (dd, J=12.6, 7.2 Hz, 1 H), 8.21 (d, J=5.7 Hz, 1 H), 7.92 (d, J=7.8 Hz, 1 H), 7.66 (d, J=2.4 Hz, 1 H) 7.51-7.48 (m, 3 H), 7.36 (t, J=8.7 Hz, 2 H), 6.76 (dd, J=5.7, 2.5 Hz, 1 H), 6.55 (d, J=7.9 Hz, 1 H), 4.28-4.27 (m, 2 H), 1.34 (t, J=6.98 Hz, 3 H), 1.05 (s, 9 H); MS (ESI) m/z: 581.2 (M+H+).

後処理

  1. customThe mixture was sparged with argon for several min
  2. temperatureThe mixture was cooled to RT
  3. filtrationfiltered
  4. washwashing with dioxane
  5. concentrationThe filtrate was concentrated to dryness
  6. customthe residue was purified by reverse-phase chromatography [10%-45% CH3CN/H2O with 0.1% TFA]
  7. extractionextracted with EtOAc
  8. washThe organic layer was washed with brine
  9. dry with materialdried over Na2SO4
  10. concentrationconcentrated

出典と根拠

ORDレコード
ord-fb2e84dac3954a25a11dd2b43ba0b53b
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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