Реакция #1498331

Уравнение реакции

Cs2CO3

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

pivalamide

Xantphos

→

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

Выход 29.7%

Растворители

dioxane

Условия реакции

Обработка

1. 1
   ДругоеThe mixture was sparged with argon for several min
2. 2
   ТемператураThe mixture was cooled to RT
3. 3
   Фильтрацияfiltered
4. 4
   Промывкаwashing with dioxane
5. 5
   КонцентрированиеThe filtrate was concentrated to dryness
6. 6
   Другоеthe residue was purified by reverse-phase chromatography [10%-45% CH3CN/H2O with 0.1% TFA]
7. 7
   Экстракцияextracted with EtOAc
8. 8
   ПромывкаThe organic layer was washed with brine
9. 9
   Сушкаdried over Na2SO4
10. 10
    Концентрированиеconcentrated

Методика

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, 1H), 9.89 (s, 1H), 8.34 (dd, J=12.6, 7.2 Hz, 1H), 8.21 (d, J=5.7 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.66 (d, J=2.4 Hz, 1H,) 7.51-7.48 (m, 3H), 7.36 (t, J=8.7 Hz, 2H), 6.76 (dd, J=5.7, 2.5 Hz, 1H), 6.55 (d, J=7.9 Hz, 1H), 4.28-4.27 (m, 2H), 1.34 (t, J=6.98 Hz, 3H), 1.05 (s, 9H); MS (ESI) m/z: 581.2 (M+H+).

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