Dimethylformamide → 6-[1-(Difluoromethoxy)-2,2,2-trifluoroethyl]-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-9-carbonitrile

HRID 1629017Notes

Reaction equation

HRID 1629017 reaction equation
Br[C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:24])=[N:17][C:18]([O:22][CH3:23])=[N:19][C:20]=4[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:25]([O:30][CH:31]([F:33])[F:32])[C:26]([F:29])([F:28])[F:27])=[CH:4][CH:3]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[CH3:55][N:56](C)C=O>C(=O)([O-])O.[Na+].[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:33][CH:31]([F:32])[O:30][CH:25]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[C:20]([CH3:21])=[N:19][C:18]([O:22][CH3:23])=[N:17][C:16]=4[CH3:24])[C:8]3=[N:9][C:10]=2[C:2]([C:55]#[N:56])=[CH:3][CH:4]=1)[C:26]([F:28])([F:27])[F:29]

Participants

7

Reactant 3

HCID 6228DimethylformamideHCID 27342152-(Di-tert-butylphosphino)biphenylHCID 577860939-Bromo-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole

Product 1

HCID 577858226-[1-(Difluoromethoxy)-2,2,2-trifluoroethyl]-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-9-carbonitrileYield 52%

Reagents, catalysts & solvents 3

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 516892Sodium BicarbonateSolvent

Conditions

Temperature
120 °C

Procedure

A mixture of 9-bromo-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (254 mg, 0.474 mmol), zinc cyanide (557 mg, 4.74 mmol), 2-(di-tert-butylphosphino)biphenyl (14.1 mg, 0.0474 mmol), and tris(dibenzylideneacetone)dipalladium (43.4 mg, 0.0474 mmol) in N,N-dimethylformamide (2.4 ml) was stirred at 120° C. under nitrogen for 7 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 75-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give a solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as colorless crystals (118 mg, 0.245 mmol, 52%).

Workup

  1. extractionextracted with ethyl acetate
  2. washThe combined organic layer was washed with brine
  3. dry with materialdried over anhydrous magnesium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified by flash column chromatography on silica gel eluting with a 75-100% ethyl acetate/n-hexane gradient mixture
  7. concentrationThe filtrate was concentrated in vacuo
  8. customto give a solid, which
  9. customwas recrystallized from ethyl acetate/n-hexane

Sources & evidence

ORD record
ord-6e62e97ccde4407aa229ab8f38087995
Source dataset
uspto-grants-2014_07
Patent number
US08785460B2

Reaction notes

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