Sodium Hydroxide → 4-(4-bromo-2-(difluoromethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-yl)morpholine

HRID 1622483Notes

Reaction equation

HRID 1622483 reaction equation
[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]([F:13])[F:12])[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:16]=3[CH3:25])[C:6]=2[CH:5]=[C:4]([NH2:26])[CH:3]=1.[OH-].[Na+].Br[CH2:30][CH2:31][O:32][CH2:33][CH2:34]Br>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]([F:13])[F:12])[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[C:16]=3[CH3:25])[C:6]=2[CH:5]=[C:4]([N:26]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:3]=1

Participants

5

Reactant 3

HCID 14798Sodium HydroxideHCID 21521Bis(2-bromoethyl) etherHCID 866878414-bromo-2-(difluoromethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-amine

Product 1

HCID 866878424-(4-bromo-2-(difluoromethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-yl)morpholineYield 36.3%

Reagents, catalysts & solvents 1

HCID 67553Tetrabutylammonium IodideCatalyst

Procedure

Two combined batches of 4-bromo-2-(difluoromethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-amine (1.087 g, 2.503 mmol) was stirred in 6M sodium hydroxide (30 mL, 180 mmol) solution with 1-bromo-2-(2-bromoethoxy)ethane (1.5 mL, 12.03 mmol) and tetrabutylammonium iodide (0.092 g, 0.250 mmol) at 110° C. After stirring for 2.5 hr the mixture was cooled and the aqueous was decanted and the remaining sticky solid was dissolved in EtOAc. The organic was washed with H2O and brine and dried over MgSO4 and concentrated to leave a residue. The residue was loaded onto a 25 g Silica column and eluted with a EtOAc/Hex 15% to 40% over 15 column volumes. While loading onto the column, a significant amount of solid crystallized on the silica wafer. This material was scraped off and dried in-vacuo to provide 4-(4-bromo-2-(difluoromethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-yl)morpholine (458 mg, 0.908 mmol, 36.3% yield) as a light orange solid. The material that was absorbed on the silica wafer was purified to provide additional material 4-(4-bromo-2-(difluoromethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-yl)morpholine (300 mg, 0.595 mmol, 23.76% yield). The total yield desired product was 758 mg (60%). LC/MS: MS (ES+) m/e 503.9 [M+H]+; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.61 (d, J=7.83 Hz, 1H), 7.25-7.32 (d, J=1.77 Hz, 1H), 7.16 (t, J=7.83 Hz, 1H), 6.83-7.13 (m, 1H), 6.59 (d, J=7.58 Hz, 1H), 6.38 (d, J=1.77 Hz, 1H), 5.55 (s, 2H), 3.77-3.92 (m, 4H), 3.05-3.16 (m, 4H), 2.56 (s, 3H)

Workup

  1. temperaturewas cooled
  2. customthe aqueous was decanted
  3. dissolutionthe remaining sticky solid was dissolved in EtOAc
  4. washThe organic was washed with H2O and brine
  5. dry with materialdried over MgSO4
  6. concentrationconcentrated
  7. customto leave a residue
  8. washeluted with a EtOAc/Hex 15% to 40% over 15 column volumes
  9. customa significant amount of solid crystallized on the silica
  10. customdried in-vacuo

Sources & evidence

ORD record
ord-e4d09d5c14b24b2699f3af3722090f66
Source dataset
uspto-grants-2014_07
Patent number
US08778937B2

Reaction notes

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