反应详情

温度

100 °C

N-(4-(2-Chloropyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (200 mg, 0.43 mmol) (as prepared in Example 1), propionamide (95 mg, 1.30 mmol), xantphos (25 mg, 0.043 mmol), and cesium carbonate (280 mg, 0.86 mmol) were dissolved in dry dioxane (3 mL) and argon was bubbled through the mixture for 10 minutes. Pd2(dba)3 (20 mg, 0.022 mmol) was then added, and the solution was degassed for an additional 10 minutes. The flask was fitted with a balloon of N2 and slowly heated to 100° C. and stirred overnight. The reaction mixture was cooled to room temperature and diluted with a 4:1 mixture of ethyl acetate and THF (60 mL) and water (40 mL). The organic layer was separated and washed with brine and the aqueous layer was back extracted with the ethyl acetate/THF solution, which was then extracted with brine. The combined organic layers were dried over sodium sulfate and evaporated and the residue was purified by silica gel chromatography to give N-(2,5-difluoro-4-(2-propionamidopyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (130 mg, 60.7% yield). 1H-NMR (400 MHz, DMSO-d6): δ 11.00 (s, 1H), 10.52 (s, 1H), 9.79 (s, 1H), 8.19 (d, 5.6 Hz, 1H), 8.10-8.05 (m, 1H), 7.66 (d, J=2.4 Hz, 1H), 7.59-7.53 (m, 3H), 7.16 (t, J=8.8 Hz, 2H), 6.74-6.72 (m, 1H), 2.33 (q, 0.7=7.2 Hz, 2H), 1.64-1.55 (m, 4H), 0.99 (t, J=7.2 Hz, 3H).

1. customargon was bubbled through the mixture for 10 minutes
2. customthe solution was degassed for an additional 10 minutes
3. customThe flask was fitted with a balloon of N2
4. temperatureThe reaction mixture was cooled to room temperature
5. additiondiluted with a 4:1 mixture of ethyl acetate and THF (60 mL) and water (40 mL)
6. customThe organic layer was separated
7. washwashed with brine
8. extractionthe aqueous layer was back extracted with the ethyl acetate/THF solution, which
9. extractionwas then extracted with brine
10. dry with materialThe combined organic layers were dried over sodium sulfate
11. customevaporated
12. customthe residue was purified by silica gel chromatography