Water → (RS)-1-[2-(5,6-Difluoro-1-methyl-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

HRID 2378019Notes

Reaction equation

HRID 2378019 reaction equation
[F:1][C:2]1[C:32]([F:33])=[CH:31][C:5]2[NH:6][C:7]([CH2:9][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][N:11]3[C:16]([C:18]3[N:19]=[C:20]([CH3:30])[S:21][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:17])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].I[CH3:37].O>CN(C=O)C.Cl>[F:1][C:2]1[C:32]([F:33])=[CH:31][C:5]2[N:6]([CH3:37])[C:7]([CH2:9][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][N:11]3[C:16]([C:18]3[N:19]=[C:20]([CH3:30])[S:21][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:17])=[N:8][C:4]=2[CH:3]=1

Participants

7

Reactant 4

HCID 962WaterHCID 6328Methyl iodideHCID 24758Sodium hydrideHCID 17973672(RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

Product 1

HCID 17973693(RS)-1-[2-(5,6-Difluoro-1-methyl-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoneYield 34%

Reagents, catalysts & solvents 2

HCID 313Hydrochloric AcidCatalystHCID 6228DimethylformamideSolvent

Procedure

(RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone, E35 (400 mg, 0.85 mmol) was slowly added to an ice-cooled slurry of NaH (68 mg, 60% dispersion on mineral oil, 1.7 mmol) in DMF (10 ml). After 0.5 h iodomethane (0.90 mmol) was added. The reaction mixture was stirred at room temperature, under argon for 16 h. 2N HCl (9 drops) then water (100 ml) were added. The aqueous phase was extracted with EtOAc(2×) and the combined organics washed with brine, dried (Na2SO4) and the solvent removed in vacuo. The residue was chromatographed (silica gel, 50-100% pentane-ethyl acetate). Residual DMF was removed by dissolving in ethyl acetate/diethyl ether and washing with water (2×). Drying (Na2SO4) and removal of the solvent in vacuo afforded the title compound as a pale yellow solid (142 mg, 34%).

Workup

  1. extractionThe aqueous phase was extracted with EtOAc(2×)
  2. washthe combined organics washed with brine
  3. dry with materialdried (Na2SO4)
  4. customthe solvent removed in vacuo
  5. customThe residue was chromatographed (silica gel, 50-100% pentane-ethyl acetate)
  6. customResidual DMF was removed
  7. dissolutionby dissolving in ethyl acetate/diethyl ether
  8. washwashing with water (2×)
  9. customDrying
  10. custom(Na2SO4) and removal of the solvent in vacuo

Sources & evidence

ORD record
ord-05aa5d806c0d457abaf228979374f8b2
Source dataset
uspto-grants-2008_12
Patent number
US07470710B2

Reaction notes

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