Dimethylformamide → tert-butyl {(1S)-2-[(6-{6-[(2,2-difluorocyclopropyl)methoxy]-1,3-benzoxazol-2-yl}-5-fluoropyridin-3-yl)oxy]-1-methylethyl}carbamate

HRID 1026328Notes

Reaction equation

HRID 1026328 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[O-:24])[CH3:21])[CH:5]=[N:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=2[N:12]=1.CS(O[CH2:31][CH:32]1[CH2:34][C:33]1([F:36])[F:35])(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:35][C:33]1([F:36])[CH2:34][CH:32]1[CH2:31][O:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:7]3[N:6]=[CH:5][C:4]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:24])[O:25][C:32]([CH3:34])([CH3:33])[CH3:31])[CH3:21])=[CH:3][C:2]=3[F:1])[O:9][C:10]=2[CH:16]=1

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 11430Potassium Carbonate3×HCID 58198163Cyclopropanemethanol, 2,2-difluoro-, 1-methanesulfonate3×HCID 136372366[(1S)-2-{[5-fluoro-6-(6-hydroxy-1,3-benzoxazol-2-yl)pyridin-3-yl]oxy}-1-methylethyl]carbamate

Product 1

HCID 86666313tert-butyl {(1S)-2-[(6-{6-[(2,2-difluorocyclopropyl)methoxy]-1,3-benzoxazol-2-yl}-5-fluoropyridin-3-yl)oxy]-1-methylethyl}carbamate

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
60 °C

Procedure

Triethylamine (14.1 mL) was added to a solution of hexachloroethane (7.46 g) and triphenylphosphine (9.91 g) in acetonitrile (50 mL) at room temperature, and the mixture was stirred at room temperature for 10 min. Then a mixture of tert-butyl [(1S)-2-({6-[(2,4-dihydroxyphenyl)carbamoyl]-5-fluoropyridin-3-yl}oxy)-1-methylethyl]carbamate (5.31 g) and acetonitrile (50 mL) was added, and the mixture was stirred at room temperature for 2 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give tert-butyl [(1S)-2-{[5-fluoro-6-(6-hydroxy-1,3-benzoxazol-2-yl)pyridin-3-yl]oxy}-1-methylethyl]carbamate (10.7 g) as a mixture with impurities. A mixture of [(1S)-2-{[5-fluoro-6-(6-hydroxy-1,3-benzoxazol-2-yl)pyridin-3-yl]oxy}-1-methylethyl]carbamate (4.28 g, a mixture with impurities), (2,2-difluorocyclopropyl)methyl methanesulfonate (0.494 g), potassium carbonate (0.367 g), and DMF (30 mL) was stirred at 60° C. for 1 hr. Then additional (2,2-difluorocyclopropyl)methyl methanesulfonate (0.494 g) and potassium carbonate (0.367 g) were added, and the mixture was stirred at 60° C. for 1 hr. Then additional (2,2-difluorocyclopropyl)methyl methanesulfonate (0.494 g) and potassium carbonate (0.367 g) were added, and the mixture was stirred at 60° C. for 1 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.39 g) as a pale yellow solid.

Workup

  1. stirringthe mixture was stirred at 60° C. for 1 hr
  2. extractionthe mixture was extracted with ethyl acetate
  3. customThe organic layer was separated
  4. washwashed with brine
  5. dry with materialdried over anhydrous magnesium sulfate
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified by silica gel column chromatography (hexane/ethyl acetate)

Sources & evidence

ORD record
ord-36d8dcc778ff445d90b7f2b1714df4f7
Source dataset
uspto-grants-2014_05
Patent number
US08729102B2

Reaction notes

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