Sodium Azide → N-((4S,6S)-4-(5-amino-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide

HRID 930279Notes

Reaction equation

HRID 930279 reaction equation
O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[N-]=[N+]=[N-].[Na+].Br[C:19]1[CH:20]=[CH:21][C:22]([F:46])=[C:23]([C@:25]2([CH2:44][F:45])[CH2:30][C@@H:29]([C:31]([F:34])([F:33])[F:32])[O:28][C:27]([NH:35][C:36](=[O:43])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[N:26]2)[CH:24]=1.C[NH:48][C@@H]1CCCC[C@H]1NC.[BH4-].[Na+]>[Cu]I.O>[NH2:48][C:19]1[CH:20]=[CH:21][C:22]([F:46])=[C:23]([C@:25]2([CH2:44][F:45])[CH2:30][C@@H:29]([C:31]([F:34])([F:33])[F:32])[O:28][C:27]([NH:35][C:36](=[O:43])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[N:26]2)[CH:24]=1

Participants

8

Reactant 5

HCID 33557Sodium AzideHCID 2733821trans-N,N'-dimethyl-1,2-cyclohexanediamineHCID 4311764Sodium borohydrideHCID 23667548Sodium AscorbateHCID 86732109N-((4S,6S)-4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide

Product 1

HCID 86732108N-((4S,6S)-4-(5-amino-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 962WaterSolvent

Conditions

Temperature
80 °C

Procedure

A sealable vial was charged with (+)-sodium L-ascorbate (0.048 g, 0.241 mmol, Arcos Organics), sodium azide (0.470 g, 7.20 mmol, Aldrich), copper(I) iodide (0.138 g, 0.723 mmol, Aldrich), and N-((4S,6S)-4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (1.15 g, 2.41 mmol, step 8). The sealed vial was evacuated and backfilled with nitrogen gas. EtOH (5.62 ml) was added followed by water (2.41 ml) and trans-N,N′-dimethylcyclohexane-1,2-diamine (0.069 g, 0.482 mmol). The reaction was stirred in a pre-heated 80° C. oil bath for 16 hours. The reaction mixture was cooled to RT and partitioned between water and EtOAc. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude residue was taken up in MeOH (20 mL) and sodium borohydride (0.091 g, 2.41 mmol, Aldrich) was added. The reaction was stirred at room temperature for 30 minutes. The reaction was quenched with water and further diluted with water and EtOAc. The organic layer was washed three times with a solution of aqueous saturated ammonium hydroxide and aqueous saturated ammonium chloride solution (1:9), and brine. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure to afford the crude title compound as a grey oil, which was used without further purification assuming theoretical yield. MS m/z=413.9 [M+H]+. Calculated for C19H16F5N3O2: 413.341.

Workup

  1. customThe sealed vial was evacuated
  2. additionEtOH (5.62 ml) was added
  3. temperatureThe reaction mixture was cooled to RT
  4. custompartitioned between water and EtOAc
  5. washThe organic layer was washed with brine
  6. dry with materialdried over magnesium sulfate
  7. concentrationconcentrated under reduced pressure
  8. stirringThe reaction was stirred at room temperature for 30 minutes
  9. customThe reaction was quenched with water
  10. additionfurther diluted with water and EtOAc
  11. washThe organic layer was washed three times with a solution of aqueous saturated ammonium hydroxide and aqueous saturated ammonium chloride solution (1:9), and brine
  12. dry with materialThe organic phase was dried over magnesium sulfate
  13. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-3e3edee38c6248ac89c34e37305d0018
Source dataset
uspto-grants-2016_03
Patent number
US09296734B2

Reaction notes

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