Acetone Cyanohydrin → 4-{4-[6-Methyl-2-oxo-5-(trifluoromethyl)-2,3-dihydro-1H-benzimidazol-1-yl]-1-piperidinyl}tetrahydro-2H-pyran-4-carbonitrile

HRID 2064175Notes

Reaction equation

HRID 2064175 reaction equation
[CH3:1][C:2]1[C:3]([C:18]([F:21])([F:20])[F:19])=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:6]=2[CH:17]=1.O[C:23]([CH3:27])([CH3:26])[C:24]#[N:25].[O:28]1[CH2:33]CC(=O)C[CH2:29]1.[O-]S([O-])(=O)=O.[Mg+2]>ClCCl.O.CN(C)C(=O)C>[CH3:1][C:2]1[C:3]([C:18]([F:19])([F:21])[F:20])=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:12][CH2:13][N:14]([C:23]4([C:24]#[N:25])[CH2:27][CH2:33][O:28][CH2:29][CH2:26]4)[CH2:15][CH2:16]3)[C:6]=2[CH:17]=1

Participants

7

Reactant 4

HCID 6406Acetone CyanohydrinHCID 24083Sulfuric acid magnesium salt (1:1)HCID 121599Tetrahydro-4H-pyran-4-oneHCID 59850150HCID 59850150, compound

Product 1

HCID 598501404-{4-[6-Methyl-2-oxo-5-(trifluoromethyl)-2,3-dihydro-1H-benzimidazol-1-yl]-1-piperidinyl}tetrahydro-2H-pyran-4-carbonitrileYield 73.3%

Reagents, catalysts & solvents 2

HCID 31374DimethylacetamideSolventHCID 21908982Water methylene chlorideSolvent

Procedure

6-Methyl-1-(4-piperidinyl)-5-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one (free base of D60, 0.473 g, 1.47 mmol), 2-hydroxy-2-methylpropanenitrile (2 eq., 2.94 mmol, 0.268 ml), tetrahydro-4H-pyran-4-one (2 eq., 2.94 mmol, 0.27 ml), MgSO4 (880 mg) and N,N-dimethylacetamide (4 ml) were heated at 60° C. under argon for 24 hours. The mixture was subsequently cooled to room temperature and dichloromethane/water (70 ml/70 ml) were added and the biphasic mixture obtained was sonicated at room temperature for 20 minutes. The two phases were separated and the organic phase was dried by hydromatrix cartridge. The organic solvent was subsequently evaporated and the solid obtained was triturated with diethyl ether to afford the title compound (440 mgs, 70%).

Workup

  1. customthe biphasic mixture obtained
  2. customwas sonicated at room temperature for 20 minutes
  3. customThe two phases were separated
  4. customthe organic phase was dried by hydromatrix cartridge
  5. customThe organic solvent was subsequently evaporated
  6. customthe solid obtained
  7. customwas triturated with diethyl ether

Sources & evidence

ORD record
ord-a267fdebd6254ec9b92a15f30b8f24fa
Source dataset
uspto-grants-2012_10
Patent number
US08288412B2

Reaction notes

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