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

HRID 1622470Notes

Reaction equation

HRID 1622470 reaction equation
[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][F:12])[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:15]=3[CH3:24])[C:6]=2[CH:5]=[C:4]([NH2:25])[CH:3]=1.[OH-].[Na+].Br[CH2:29][CH2:30][O:31][CH2:32][CH2:33]Br>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][F:12])[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[C:15]=3[CH3:24])[C:6]=2[CH:5]=[C:4]([N:25]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:3]=1

Participants

5

Reactant 3

HCID 14798Sodium HydroxideHCID 21521Bis(2-bromoethyl) etherHCID 866878314-bromo-2-(fluoromethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-amine

Product 1

HCID 866878324-(4-bromo-2-(fluoromethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-yl)morpholineYield 33.9%

Reagents, catalysts & solvents 1

HCID 67553Tetrabutylammonium IodideCatalyst

Conditions

Temperature
110 °C

Procedure

Into a 100 ml round bottomed flask with 4-bromo-2-(fluoromethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-amine (2.3 g, 5.53 mmol), tetrabutylammonium iodide (0.102 g, 0.276 mmol) was added 6N sodium hydroxide (13.82 ml, 83 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (1.378 ml, 11.05 mmol). Reaction was heated to 110° C. for 2 h then cooled to room temperature and the mixture was extracted with EtOAc, washed with Brine and concentrated. The residue was purified on a silica gel cartridge and eluted with a gradient of 0% ethyl acetate/hexanes to 50% over 10 column volumes. The appropriate fractions were collected and evaporated to yield 4-(4-bromo-2-(fluoromethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-yl)morpholine (911 mg, 1.873 mmol, 33.9% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.51 (s, 3H) 3.04-3.11 (m, 4H) 3.77-3.85 (m, 4H) 5.40 (s, 2H) 5.42-5.60 (m, 2H) 6.45 (d, J=2.02 Hz, 1H) 6.53 (d, 1H) 7.12 (t, J=7.83 Hz, 1H) 7.21 (d, J=2.02 Hz, 1H) 7.56 (d, J=7.83 Hz, 1H); LC/MS: MS (ES+) m/e 487 [M+H]+.

Workup

  1. customReaction
  2. temperaturethen cooled to room temperature
  3. extractionthe mixture was extracted with EtOAc
  4. washwashed with Brine
  5. concentrationconcentrated
  6. customThe residue was purified on a silica gel cartridge
  7. washeluted with a gradient of 0% ethyl acetate/hexanes to 50% over 10 column volumes
  8. customThe appropriate fractions were collected
  9. customevaporated

Sources & evidence

ORD record
ord-cb59836731c34ba9b360866bc3e6564b
Source dataset
uspto-grants-2014_07
Patent number
US08778937B2

Reaction notes

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