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

HRID 2400579
Notes
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Reaction equation

HRID 2400579 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:14]=[C:13]([CH3:15])[N:12]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[N:11]=3)[N:7](COCC[Si](C)(C)C)[C:6]=2[CH:32]=1.[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+].O=O>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:2]2[CH:3]=[CH:4][C:5]3[N:9]=[C:8]([C:10]4[CH:14]=[C:13]([CH3:15])[N:12]([CH2:16][C:17]5[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=5)[N:11]=4)[NH:7][C:6]=3[CH:32]=2)=[CH:36][CH:35]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

8

Reactant 4

HCID 977OxygenHCID 10340Sodium CarbonateHCID 2856454-Fluorophenylboronic acidHCID 595047146-Bromo-2-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole

Product 1

HCID 1358760176-(4-Fluorophenyl)-2-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1H-benzimidazoleYield 38.3%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

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.

Workup

  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

Sources & evidence

ORD record
ord-039c1732396249ca9fd415faf9a975b0
Source dataset
uspto-grants-2014_08
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08796253B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes