Oxygen → 6-(4-Fluorophenyl)-2-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1H-benzimidazole

To a solution of 6-bromo-2-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (Step 1, 150 mg, 0.29 mmol) in dioxane (5 mL) was added (4-fluorophenyl)boronic acid (49 mg, 0.35 mmol) followed by sodium carbonate solution (2.0 M aq., 0.44 mL, 0.88 mmol), and the resultant mixture was freed from oxygen by bubbling a gentle stream of nitrogen through the solution for 10 min. Tetrakis(triphenylphosphine)palladium(0) (34 mg, 0.03 mmol) was then added and the mixture was refluxed for 5 hr. After being cooled to rt, the mixture was diluted with ethyl acetate (50 mL) and washed with water (1×25 mL). The combined organics were dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting crude material was suspended in dichloromethane (2 mL), TFA (2 mL) was added, and the mixture was stirred at rt for 16 h. The volatiles were removed under reduced pressure and the crude product was purified by HPLC eluting with a gradient from 20% to 80% acetonitrile in water containing 0.1% TFA. The combined fractions were then diluted with ethyl acetate and washed with sat. NaHCO3 solution (1×50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to afford the title compound as a light yellow solid (44 mg, 38%): 1H NMR (300 MHz, CD3OD) δ 7.75 (bs, 1H), 7.63-7.69 (m, 3H), 7.52 (dd. 1H), 7.11-7.20 (m, 6H), 6.78 (s, 1H), 5.40 (s, 2H), 2.30 (s, 6H); ES-MS m/z 397.22, HPLC RT (Method B) 3.21 min.

1. customby bubbling a gentle stream of nitrogen through the solution for 10 min
2. temperaturethe mixture was refluxed for 5 hr
3. washwashed with water (1×25 mL)
4. dry with materialThe combined organics were dried (Na2SO4)
5. filtrationfiltered
6. concentrationconcentrated under reduced pressure
7. additionTFA (2 mL) was added
8. customThe volatiles were removed under reduced pressure
9. customthe crude product was purified by HPLC
10. washeluting with a gradient from 20% to 80% acetonitrile in water containing 0.1% TFA
11. additionThe combined fractions were then diluted with ethyl acetate
12. washwashed with sat. NaHCO3 solution (1×50 mL)
13. dry with materialdried (Na2SO4)
14. filtrationfiltered
15. concentrationconcentrated under reduced pressure

ORD-Eintrag

ord-039c1732396249ca9fd415faf9a975b0

Quelldatensatz

uspto-grants-2014_08

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08796253B2