Sodium Azide → tert-butyl ((1R,5S,6R)-5-(5-amino-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)carbamate

HRID 1526535Notes

Reaction equation

HRID 1526535 reaction equation
[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[O:9][C@H:10]2[C@@H:12]([C@:13]([C:18]3[CH:23]=[C:22](Br)[CH:21]=[CH:20][C:19]=3[F:25])([CH:15]([F:17])[F:16])[N:14]=1)[CH2:11]2)([CH3:4])([CH3:3])[CH3:2].[N-:27]=[N+]=[N-].[Na+].[NH4+].[Cl-].[OH-].[NH4+].CP(C)C>CCOC(C)=O.C1COCC1.O.[Cu]I.CCO>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[O:9][C@H:10]2[C@@H:12]([C@:13]([C:18]3[CH:23]=[C:22]([NH2:27])[CH:21]=[CH:20][C:19]=3[F:25])([CH:15]([F:17])[F:16])[N:14]=1)[CH2:11]2)([CH3:4])([CH3:3])[CH3:2]

Participants

10

Reactant 4

HCID 33557Sodium AzideHCID 68983TrimethylphosphineHCID 21863491Ammonium chloride ammonium hydroxideHCID 90401263tert-butyl ((1R,5S,6R)-5-(5-bromo-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)carbamate

Product 1

HCID 131733175tert-butyl ((1R,5S,6R)-5-(5-amino-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)carbamateYield 82%

Reagents, catalysts & solvents 5

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 702EthanolSolventHCID 962WaterSolvent3×HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent2×

Conditions

Temperature
70 °C

Procedure

To a mixture of tert-butyl((1R,5S,6R)-5-(5-bromo-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)carbamate (16h-B, 1.47 g, 3.38 mmol), copper(I) iodide (0.139 g, 0.730 mmol), (+)-sodium 1-ascorbate (0.131 g, 0.661 mmol), and sodium azide (0.688 g, 10.6 mmol) were added EtOH (4.6 mL) and water (2.3 mL). The reaction mixture was purged with Nitrogen for 10 min, followed by the addition of (1R,2R)-(−)-N,N″-dimethylcyclohexane-1,2-diamine (0.110 mL, 0.698 mmol). The reaction mixture was heated to 70° C. for 1.5 h and cooled to RT. The reaction mixture was poured into 10:1 saturated NH4Cl/ammonium hydroxide, and diluted with EtOAc. The aqueous phase was extracted with EtOAc (2×) and the combined organic extracts were washed with brine and dried over MgSO4. The filtrate was concentrated under reduced pressure to give a solid, which was dissolved in THF (12 mL) and water (4 mL). A solution of trimethyl phosphine (1.0 M in THF, 3.40 mL, 3.40 mmol) was added and the reaction mixture was stirred at RT for 15 min. The reaction mixture was diluted with EtOAc and water, the aqueous phase was separated and extracted with EtOAc. The combined organic extracts were washed with brine and dried over MgSO4. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (20% to 70% EtOAc in heptane) to give the title compound (1.03 g, 2.77 mmol, 82% yield) as a white solid. MS m/z=372.0 [M+H]+. Calculated for C17H20F3N3O3 371.1.

Workup

  1. customThe reaction mixture was purged with Nitrogen for 10 min
  2. temperaturecooled to RT
  3. extractionThe aqueous phase was extracted with EtOAc (2×)
  4. washthe combined organic extracts were washed with brine
  5. dry with materialdried over MgSO4
  6. concentrationThe filtrate was concentrated under reduced pressure
  7. customto give a solid, which
  8. customthe aqueous phase was separated
  9. extractionextracted with EtOAc
  10. washThe combined organic extracts were washed with brine
  11. dry with materialdried over MgSO4
  12. concentrationThe filtrate was concentrated under reduced pressure
  13. customthe residue was purified by flash column chromatography on silica gel (20% to 70% EtOAc in heptane)

Sources & evidence

ORD record
ord-e1594fe6947b4f5e883f57b3459a6707
Source dataset
uspto-grants-2015_07
Patent number
US09085576B2

Reaction notes

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