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

Temperature

100 °C

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+).

1. customwas bubbled through the mixture for 15 minutes
2. customargon was bubbled through the solution for an additional 10 minutes
3. customThe round bottom flask was then fitted with a reflux condenser
4. customflushed with argon
5. temperatureAfter 3.5 hours at 100° C. the reaction mixture was cooled to room temperature
6. additionThe reaction mixture was diluted with a 4:1 mixture of ethyl acetate and THF (300 mL) and water (100 mL)
7. customA bright yellow solid was removed by suction filtration
8. customThe organic layer was separated from the aqueous and
9. washwashed with brine (200 mL)
10. extractionIn addition, the aqueous layer was back-extracted with the ethyl acetate/THE mixture (100 mL), which
11. washwas then also washed with brine (50 mL)
12. dry with materialThe combined organic layers were dried over magnesium sulfate
13. customevaporated
14. customto yield a peach-colored oil
15. customa white solid formed which
16. filtrationwas collected by suction filtration
17. washwashed with more dichloromethane

ORD record

ord-42fa2f5f8be4423b9edc4b0cd8fed555

Source dataset

uspto-grants-2014_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08637672B2