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

HRID 1622473Notes

Reaction equation

HRID 1622473 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]([Cl:20])[C:15]=3[CH3:21])[C:6]=2[CH:5]=[C:4]([NH2:22])[CH:3]=1.[OH-].[Na+].Br[CH2:26][CH2:27][O:28][CH2:29][CH2:30]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]([Cl:20])[C:15]=3[CH3:21])[C:6]=2[CH:5]=[C:4]([N:22]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:3]=1

Participants

5

Reactant 3

HCID 14798Sodium HydroxideHCID 21521Bis(2-bromoethyl) etherHCID 866878344-bromo-1-(3-chloro-2-methylbenzyl)-2-(fluoromethyl)-1H-benzo[d]imidazol-6-amine

Product 1

HCID 866878354-(4-bromo-1-(3-chloro-2-methylbenzyl)-2-(fluoromethyl)-1H-benzo[d]imidazol-6-yl)morpholineYield 26.4%

Reagents, catalysts & solvents 1

HCID 67553Tetrabutylammonium IodideCatalyst

Conditions

Temperature
110 °C

Procedure

Into a 100 ml round bottomed flask with 4-bromo-1-(3-chloro-2-methylbenzyl)-2-(fluoromethyl)-1H-benzo[d]imidazol-6-amine (2.49 g, 6.51 mmol), tetrabutylammonium iodide (0.120 g, 0.325 mmol) was added 6N sodium hydroxide (16.27 ml, 98 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (1.623 ml, 13.01 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 by reversed phase eluted with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (35-65%) over 12 minutes. The expected compound was collected and evaporated to yield a colorless oil 4-(4-bromo-1-(3-chloro-2-methylbenzyl)-2-(fluoromethyl)-1H-benzo[d]imidazol-6-yl)morpholine (777 mg, 1.716 mmol, 26.4% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.50 (s, 3H) 3.12-3.18 (m, 4H) 3.78-3.86 (m, 4H) 5.55-5.71 (m, 4H) 6.37 (d, J=8.08 Hz, 1H) 6.84 (d, J=2.02 Hz, 1H) 7.06 (t, J=8.08 Hz, 1H) 7.36 (d, J=8.08 Hz, 1H) 7.39 (d, 1H); LC/MS: MS (ES+) m/e 453 [M+H]+.

Workup

  1. temperaturethen cooled to room temperature
  2. extractionthe mixture was extracted with EtOAc
  3. washwashed with Brine
  4. concentrationconcentrated
  5. customThe residue was purified by reversed phase
  6. washeluted with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (35-65%) over 12 minutes
  7. customThe expected compound was collected
  8. customevaporated

Sources & evidence

ORD record
ord-2764e59741894d5a95d0417a538fb601
Source dataset
uspto-grants-2014_07
Patent number
US08778937B2

Reaction notes

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