Potassium Carbonate → HCID 72944332, compound

Temperature

80 °C

3-Bromo-5-(1-methyl-1H-pyrazol-4-yl)-phenol (337 mg; 1.09 mmol; 1.0 eq.), bis(pinacolato)diborane (245 mg; 0.96 mmol; 0.9 eq.), 1,1-Bis(diphenylphosphino)ferrocenedichloropalladium(II) (98 mg; 0.13 mmol; 0.12 eq.) and Potassium acetate (432 mg; 4.40 mmol; 4.0 eq.) were suspended in 1,4 dioxane (8 mL). The reaction suspension was degassed with argon and heated in MW at 80° C. for 30 min. A further portion of bis(pinacolato)diborane (108 mg; 0.43 mmol; 0.4 eq.) was added and heating repeated (80° C. for 30 min in MW). Tert-butyl 4-[4-(2-iodopyrimidin-5-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (intermediate 6, 265 mg; 0.58 mmol; 0.53 eq.), bis(triphenylphosphine)palladium(II) chloride (100 mg; 0.14 mmol; 0.13 eq.) and potassium carbonate (446 mg; 3.23 mmol; 3.0 eq.) were added in one portion and the reaction solution diluted with water (3 mL), degassed with argon and heated again in MW at 100° C. for 30 min. The reaction mixture was cooled down to RT and diluted with DCM. It was filtered through celite. Organic phase was washed sequentially with a 1 N HCl solution and brine, dried over magnesium sulfate, filtered and concentrated. This crude was purified by flash chromatography on silica (n-heptane:EtOAc, gradient from 95:5 to 75:25) and then redissolved in MeOH and HCl/dioxane (10 mL of a 4N solution; 40 mmol; 37 eq.). Reaction mixture was stirred at RT for 2 h and concentrated under reduced pressure. Purification by autopreparative LC/MS afforded the title compound as a white foam (11 mg, 4%). 1H NMR (300 MHz, DMSO-d6) δ 9.67 (s, 1H), 9.16 (s, 2H), 8.50 (s, 1H), 8.18 (d, J=4.1 Hz, 2H), 8.00 (t, J=1.5 Hz, 1H), 7.83 (d, J=0.7 Hz, 1H), 7.71-7.67 (m, 1H), 7.10-7.05 (m, 1H), 4.62-4.48 (m, 1H), 3.88 (s, 3H), 3.47-3.35 (m, 2H), 3.15-3.01 (m, 2H), 2.32-2.04 (m, 4H). HPLC (Condition A): Rt 1.86 min (purity 91.2%). MS (ESI+): 402.5.

1. customThe reaction suspension was degassed with argon
2. temperatureheating
3. custom(80° C. for 30 min in MW)
4. customdegassed with argon
5. temperatureheated again in MW at 100° C. for 30 min
6. temperatureThe reaction mixture was cooled down to RT
7. additiondiluted with DCM
8. filtrationIt was filtered through celite
9. washOrganic phase was washed sequentially with a 1 N HCl solution and brine
10. dry with materialdried over magnesium sulfate
11. filtrationfiltered
12. concentrationconcentrated
13. customThis crude was purified by flash chromatography on silica (n-heptane:EtOAc, gradient from 95:5 to 75:25)
14. dissolutionredissolved in MeOH
15. customReaction mixture
16. concentrationconcentrated under reduced pressure
17. customPurification by autopreparative LC/MS

ORD record

ord-dcc3eea1c68f4c43819d96c19c31de61

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09216991B2