1,1-Dimethylethyl 4-({[(2-bromo-6-fluoro-4-methylphenyl)amino]-carbonyl}amino)-1-piperidinecarboxylate → 1,1-Dimethylethyl 4-(4-fluoro-6-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinecarboxylate

HRID 2061467Notes

Reaction equation

HRID 2061467 reaction equation
Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]([NH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[O:12]>O1CCOCC1.C(OCC)(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:9][C:4]1[C:3]2[NH:10][C:11](=[O:12])[N:13]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[C:2]=2[CH:7]=[C:6]([CH3:8])[CH:5]=1

Participants

5

Reactant 1

HCID 596832681,1-Dimethylethyl 4-({[(2-bromo-6-fluoro-4-methylphenyl)amino]-carbonyl}amino)-1-piperidinecarboxylate

Product 1

HCID 596832531,1-Dimethylethyl 4-(4-fluoro-6-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinecarboxylate

Reagents, catalysts & solvents 3

HCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

Under an argon atmosphere, bis(3,5,3′,5′-dimethoxy-dibenzylideneacetone) palladium (0) (6% mol, 1.1 mmol, 0.9 g), 1,1′-bis(diphenylphosphino)ferrocene (6% mol, 0.61 g), NatBuO (2 eq., 36 mmol, ˜3.5 g), were all dissolved in 1,4-dioxane (40 ml) and the system was purged through with argon. The mixture was stirred at room temperature for 15 minutes and 1,1-dimethylethyl 4-({[(2-bromo-6-fluoro-4-methylphenyl)amino]-carbonyl}amino)-1-piperidinecarboxylate (D32) (7.7 g, 17.9 mmol) was added at room temperature and the mixture was heated to 80° C. for 1.5 hours and then to 100° C. for extra 2 hours; the mixture was then cooled to room temperature, diluted with ethyl acetate and the organic phase obtained was washed with water and brine. Organics were dried over Na2SO4, filtered and the solvent was evaporated to afford the crude product that was purified by chromatography (ethyl acetate-n-hexane) to afford the title compound, 4.3 g, 70%, pale-grey solid, M+−H=348.

Workup

  1. customthe system was purged through with argon
  2. temperaturethe mixture was heated to 80° C. for 1.5 hours
  3. waitto 100° C. for extra 2 hours
  4. temperaturethe mixture was then cooled to room temperature
  5. customthe organic phase obtained
  6. washwas washed with water and brine
  7. dry with materialOrganics were dried over Na2SO4
  8. filtrationfiltered
  9. customthe solvent was evaporated
  10. customto afford the crude product that
  11. customwas purified by chromatography (ethyl acetate-n-hexane)

Sources & evidence

ORD record
ord-fcf858145e1a4ae39a445f7f07acd900
Source dataset
uspto-grants-2012_10
Patent number
US08283364B2

Reaction notes

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