2,6-Di-tert-butyl-4-methylphenol → HCID 46183920, compound

HRID 2386911Notes

Reaction equation

HRID 2386911 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH2:19][CH2:20][NH:21][C:22]2[C:31]3[C:26](=[C:27]([F:33])[CH:28]=[CH:29][C:30]=3[F:32])[N:25]=[CH:24][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=1.[CH:34]([Sn](CCCC)(CCCC)CCCC)=[CH2:35].C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[F:32][C:30]1[CH:29]=[CH:28][C:27]([F:33])=[C:26]2[C:31]=1[C:22]([NH:21][CH2:20][CH2:19][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]3[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=3)=[C:2]([CH:34]=[CH2:35])[CH:3]=1)=[N:23][CH:24]=[N:25]2

Participants

7

Reactant 4

HCID 314042,6-Di-tert-butyl-4-methylphenolHCID 81998TributylvinyltinHCID 821241,4-Bis(diphenylphosphino)butaneHCID 46184153HCID 46184153, compound

Product 1

HCID 46183920HCID 46183920, compoundYield 46.7%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalyst2×HCID 1140TolueneSolvent

Procedure

{2-[3-Bromo-4-(4-trifluoromethylpyridin-2-yloxy)-phenyl]-ethyl}-(5,8-difluoroquinazolin-4-yl)-amine (890 mg, 1.7 mmol), vinyl tri-n-butyltin (591 mg, 544 μL, 1.9 mmol), 1,4-bis(diphenylphosphino)butane (145 mg, 0.3 mmol), 2,6-di-tert-butyl-4-methylphenol (75 mg, 0.3 mmol) and Pd(OAc)2 (49 mg, 0.22 mmol) were added to a Carousel reactor tube containing toluene (5 mL) and fitted with a magnetic stir bar and a dry nitrogen gas line. The reaction mixture was heated to reflux. After 20 h, more Pd(OAc)2 (49 mg, 0.22 mmol) was added, and heating was continued. After another 20 h, the reaction was cooled. The reaction mixture was washed sequentially with water and brine, then dried (Na2SO4), filtered through a silica gel and Celite plug, and concentrated in vacuo. The residue was partitioned between acetonitrile (30 mL) and pentane (5×20 mL). The acetonitrile fraction then was purified by normal phase chromatography (silica gel with ethyl acetate/cyclohexane eluent) and reverse phase chromatography (C-18 solid phase with acetonitrile/water eluent, 0.5% H3PO4) to provide (5,8-difluoroquinazolin-4-yl)-{2-[4-(4-trifluoromethylpyridin-2-yloxy)-3-vinylphenyl]-ethyl}-amine as a white powder (375 mg), M.P. 86°. 1H NMR (CDCl3): δ 8.7 (s, 1H), 8.31 (d, 1H), 7.54 (d, 1H), 7.35 (m, 1H), 7.24 (m, 1H), 7.18 (m, 1H), 7.14 (s, 1H), 7.06 (d, 1H), 6.78 (bm, 2H), 5.76 (d, 1H), 5.26 (d, 1H), 3.97 (m, 2H), 3.07 (t, 2H). MS: m/z 472.

Workup

  1. customfitted with a magnetic stir bar
  2. temperatureThe reaction mixture was heated to reflux
  3. temperatureheating
  4. waitAfter another 20 h
  5. temperaturethe reaction was cooled
  6. washThe reaction mixture was washed sequentially with water and brine
  7. dry with materialdried (Na2SO4)
  8. filtrationfiltered through a silica gel and Celite plug
  9. concentrationconcentrated in vacuo
  10. customThe residue was partitioned between acetonitrile (30 mL) and pentane (5×20 mL)
  11. customThe acetonitrile fraction then was purified by normal phase chromatography (silica gel with ethyl acetate/cyclohexane eluent)

Sources & evidence

ORD record
ord-858c7be56e5a4c85b4e5d68d8b980127
Source dataset
uspto-grants-2012_09
Patent number
US08268843B2

Reaction notes

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