Sodium Carbonate → Methyl 5-fluoro-2-(pyrimidin-2-yl)benzoate

Temperatur

74 °C

To a 250 mL round-bottomed flask, was added 5-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (5.9 g, 21.06 mmol) in 2-methyl-THF (50 mL). To the resulting solution was added 2-chloropyrimidine (2.9 g, 25.28 mmol), sodium carbonate (6.7 g, 63.19 mmol), and water (17 mL). The mixture was degassed for 30 minutes. PdCl2(dppf)-dcm adduct (0.688 g, 0.843 mmol) was added and the reaction mixture was degassed once more for 30 minutes. The reaction mixture was warmed to 74° C. and stirred overnight. To the resulting solution was added diethyl ether (100 mL) and water (100 mL). The layers were thoroughly mixed separated. The aqueous layer was extracted with additional diethyl ether (100 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to a brown crude material (5.85 g, 49% desired, 2.87 actual product). The crude product was further purified through recrystallization in 10% EA/hexanes. The mixture was warmed to 70° C. and cooled slowly to room temperature. After filtration, the desired product was obtained as a brown solid (1.72 g actual product, 35% yield overall after recrystallization). 1H NMR (400 MHz, CDCl3): 8.78 (d, J=4.9 Hz, 2H), 8.09 (dd, J=8.7, 5.5 Hz, 1H), 7.39 (dd, J=8.6, 2.7 Hz, 1H), 7.30-7.20 (m, 2H), 3.77 (s, 3H).

1. customThe mixture was degassed for 30 minutes
2. customthe reaction mixture was degassed once more for 30 minutes
3. additionTo the resulting solution was added diethyl ether (100 mL) and water (100 mL)
4. additionThe layers were thoroughly mixed
5. customseparated
6. extractionThe aqueous layer was extracted with additional diethyl ether (100 mL)
7. dry with materialThe combined organics were dried over magnesium sulfate
8. filtrationfiltered
9. concentrationconcentrated under reduced pressure to a brown crude material (5.85 g, 49% desired, 2.87 actual product)
10. customThe crude product was further purified through recrystallization in 10% EA/hexanes
11. temperatureThe mixture was warmed to 70° C.
12. temperaturecooled slowly to room temperature
13. filtrationAfter filtration

ORD-Eintrag

ord-e6455dc3057d49489c2ece110037a08c

Quelldatensatz

uspto-grants-2015_06

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US09062044B2