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

HRID 1622479Notes

Reaction equation

HRID 1622479 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]([Cl:21])[C:16]=3[CH3:22])[C:6]=2[CH:5]=[C:4]([NH2:23])[CH:3]=1.[OH-].[Na+].Br[CH2:27][CH2:28][O:29][CH2:30][CH2:31]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]([Cl:21])[C:16]=3[CH3:22])[C:6]=2[CH:5]=[C:4]([N:23]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:3]=1

Participants

5

Reactant 3

HCID 14798Sodium HydroxideHCID 21521Bis(2-bromoethyl) etherHCID 866878384-bromo-1-(3-chloro-2-methylbenzyl)-2-(difluoromethyl)-1H-benzo[d]imidazol-6-amine

Product 1

HCID 866878394-(4-bromo-1-(3-chloro-2-methylbenzyl)-2-(difluoromethyl)-1H-benzo[d]imidazol-6-yl)morpholineYield 34%

Reagents, catalysts & solvents 1

HCID 67553Tetrabutylammonium IodideCatalyst

Procedure

The crude product from the previous reaction 4-bromo-1-(3-chloro-2-methylbenzyl)-2-(difluoromethyl)-1H-benzo[d]imidazol-6-amine (2.25 g, 5.62 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 (0.207 g, 0.562 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 that was purified by column chromatography. The residue was loaded onto a 25 g Silica column and eluted with EtOAc/Hex 10% to 40% over 15 minutes. The cleanest fractions containing desired product were combined and concentrated in-vacuo to afford 892 mg (34% yield) of the titled compound. LC/MS: MS (ES+) m/e 471.8 [M+H]+; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.22-7.37 (m, 3H), 6.81-7.14 (m, 2H), 6.31-6.42 (m, 2H), 5.51 (s, 2H), 3.76-3.89 (m, 4H), 3.03-3.20 (m, 4H), 2.48 (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 that
  8. customwas purified by column chromatography
  9. washeluted with EtOAc/Hex 10% to 40% over 15 minutes
  10. additionThe cleanest fractions containing desired product
  11. concentrationconcentrated in-vacuo

Sources & evidence

ORD record
ord-87d882b1d299410fbb20e23988f50846
Source dataset
uspto-grants-2014_07
Patent number
US08778937B2

Reaction notes

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