Acetamide → N-(4-(2-acetamidopyridin-4-yloxy)-2,5-difluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

Beteiligte Stoffe

Reaktionsbedingungen

Reaktionsschritte

N-(4-(2-chloropyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (3.819 g, 8.27 mmol), acetamide (2.442 g, 41.3 mmol), cesium carbonate (4.04 g, 12.40 mmol), and xantphos (0.469 g, 0.810 mmol) were stirred in dry dioxane (59.1 mL) while argon was bubbled through the mixture for 15 minutes. After this time palladium acetate (0.139 g, 0.620 mmol) was added, and argon was bubbled through the solution for an additional 10 minutes. The round bottom flask was then fitted with a reflux condenser, flushed with argon, and heated to 100° C. gradually from room temperature while under a balloon of argon. After 3.5 hours at 100° C. the reaction mixture was cooled to room temperature. The reaction mixture was diluted with a 4:1 mixture of ethyl acetate and THF (300 mL) and water (100 mL). A bright yellow solid was removed by suction filtration and discarded. The organic layer was separated from the aqueous and washed with brine (200 mL). In addition, the aqueous layer was back-extracted with the ethyl acetate/THE mixture (100 mL), which was then also washed with brine (50 mL). The combined organic layers were dried over magnesium sulfate and evaporated to yield a peach-colored oil. It was stirred in dichloromethane (50 mL) for 1.5 hours, and a white solid formed which was collected by suction filtration and washed with more dichloromethane to give N-(4-(2-acetamidopyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (3.328 g, 83% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.00 (s, 1H), 10.59 (s, 1H), 9.79 (s, 1H), 8.19 (d, 1H), 8.07 (dd, 1H), 7.65 (d, 1H), 7.57 (m, 3H), 7.16 (m, 2H), 6.71 (dd, 1H), 2.02 (s, 3H), 1.62 (m, 2H), 1.57 (m, 2H); MS (ESI) m/z: 485.1 (M+H+).

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