Trifluoroacetic acid → (S)-3-(3-(4-(1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-phenyloxazolidin-2-one

Temperature

80 °C

A solution containing (S)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-4-phenyloxazolidin-2-one (0.100 g, 0.278 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (0.334 g, 0.835 mmol) and 2M Na2CO3 (0.418 mL, 0.835 mmol) in dioxane (10 mL) was degassed with argon. Dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (13.3 mg, 0.0278 mmol) and Pd2(dba)3 (6.5 mg, 0.028 mmol), were added and the solution was degassed again with argon. The reaction vessel was sealed and heated to 80° C. for 18 hours. The cooled reaction mixture was partitioned between ethyl acetate and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification of the crude material by column chromatography, eluting with 1-5% MeOH/dichloromethane afforded the protected intermediate which was taken up in dichloromethane (2 mL). Trifluoroacetic acid (2 mL) was added and the mixture stirred at ambient temperature for 12 hours. The reaction mixture was concentrated, washed with saturated aqueous NaHCO3, extracted into ethyl acetate, dried over sodium sulfate, filtered and concentrated. Purification of the crude material by column chromatography, eluting with 2-4% MeOH/dichloromethane, afforded (S)-3-(3-(4-(1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-phenyloxazolidin-2-one as a light yellow solid, 14 mg (12%). LCMS (APCI+) m/z 423 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J=7.8 Hz, 1H), 8.65 (s, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.91 (d, J=8.6 Hz, 2H), 7.78 (d, J=8.6 Hz, 2H), 7.44-7.50 (m, 5H), 7.22 (s, 2H), 5.94-5.98 (m, 1H), 4.93 (t, J=8.6 Hz, 1H), 4.23-4.27 (m, 1H).

1. customwas degassed with argon
2. customthe solution was degassed again with argon
3. customThe reaction vessel was sealed
4. customThe cooled reaction mixture
5. customwas partitioned between ethyl acetate and brine
6. dry with materialThe organic layer was dried over sodium sulfate
7. filtrationfiltered
8. concentrationconcentrated
9. customPurification of the crude material by column chromatography
10. washeluting with 1-5% MeOH/dichloromethane
11. customafforded the protected intermediate which
12. concentrationThe reaction mixture was concentrated
13. washwashed with saturated aqueous NaHCO3
14. extractionextracted into ethyl acetate
15. dry with materialdried over sodium sulfate
16. filtrationfiltered
17. concentrationconcentrated
18. customPurification of the crude material by column chromatography
19. washeluting with 2-4% MeOH/dichloromethane

ORD record

ord-f9f81816ee43496fa680bfa9a1b8017d

Source dataset

uspto-grants-2014_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08865726B2