Potassium Carbonate → methyl 1-[(3-chloro-2-methylphenyl)methyl]-6-(4-morpholinyl)-2-(trifluoromethyl)-1H-benzimidazole-4-carboxylate

HRID 44526Notes

Reaction equation

HRID 44526 reaction equation
[N:1]1([C:7]2[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[C:10]3[NH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[N:13][C:9]=3[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[CH3:39]>CN(C)C=O>[Cl:38][C:34]1[C:33]([CH3:39])=[C:32]([CH2:31][N:13]2[C:9]3[CH:8]=[C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[C:10]=3[N:11]=[C:12]2[C:14]([F:17])([F:15])[F:16])[CH:37]=[CH:36][CH:35]=1

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 105130911-(Bromomethyl)-3-chloro-2-methylbenzeneHCID 178498369HCID 178498369, compound

Product 1

HCID 56960264methyl 1-[(3-chloro-2-methylphenyl)methyl]-6-(4-morpholinyl)-2-(trifluoromethyl)-1H-benzimidazole-4-carboxylateYield 95%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A mixture of methyl 5-(4-morpholinyl)-2-(trifluoromethyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 45 (1.5 g, 4.56 mmol) and potassium carbonate (1.889 g, 13.67 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was stirred at rt for 10 min. After addition of 1-(bromomethyl)-3-chloro-2-methylbenzene (1.500 g, 6.83 mmol), the mixture was warmed to 80° C. and stirred for 3 h at this temperature. The resulting mixture was cooled to rt and poured over ice. The precipitate formed was collected by filtration and air dried (2.4 g total). Purification on a silica gel column (10-50% EtOAc in hexane) failed to produce pure material. The fractions containing product were combined and the solvent was removed under reduced pressure to afford methyl 1-[(3-chloro-2-methylphenyl)methyl]-6-(4-morpholinyl)-2-(trifluoromethyl)-1H-benzimidazole-4-carboxylate (2.03 g, 4.34 mmol, 95% yield) (only 87% pure). A portion of this material (165 mg) was purified by RP-HPLC (25 to 95% AcCN in water, plus 0.1% TFA) to give pure desired product (92.3 mg, 0.193 mmol, 4.24% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.64 (d, J=2.27 Hz, 1H), 7.28-7.43 (m, 2H), 7.04 (t, J=7.96 Hz, 1H), 5.97 (d, J=7.83 Hz, 1H), 5.71 (s, 2H), 3.93 (s, 3H), 3.66-3.80 (m, 4H), 3.06-3.25 (m, 4H), 2.46 (s, 3H). MS (ES+) m/e 468 [M+H]+

Workup

  1. customprepared
  2. temperaturethe mixture was warmed to 80° C.
  3. stirringstirred for 3 h at this temperature
  4. temperatureThe resulting mixture was cooled to rt
  5. additionpoured over ice
  6. customThe precipitate formed
  7. filtrationwas collected by filtration and air
  8. customdried (2.4 g total)
  9. customPurification on a silica gel column (10-50% EtOAc in hexane)
  10. customto produce pure material
  11. additionThe fractions containing product
  12. customthe solvent was removed under reduced pressure

Sources & evidence

ORD record
ord-2262a0f4ca99489181c3b0414d1882bf
Source dataset
uspto-grants-2013_09
Patent number
US08541411B2

Reaction notes

Loading…