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

Temperature

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 (CAS#72287-26-4) (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 then 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% EtOAc/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. customthen separated
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% EtOAc/hexanes
11. temperatureThe mixture was warmed to 70° C.
12. temperaturecooled slowly to room temperature
13. filtrationAfter filtration

ORD record

ord-4670c9124d7a4dc79c03489356085398

Source dataset

uspto-grants-2014_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08653263B2