1,8-Diazabicyclo(5.4.0)undec-7-ene → (4S,6S)-4-(5-amino-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine

HRID 930283Notes

Reaction equation

HRID 930283 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]2([CH2:27][F:28])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH:18]C(=O)C3C=CC=CC=3)=[N:9]2)[CH:7]=1.N12CCCN=C1CCCCC2>CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]2([CH2:27][F:28])[CH2:13][C@@H:12]([C:14]([F:17])([F:15])[F:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1

Participants

4

Reactant 2

HCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 86732108N-((4S,6S)-4-(5-amino-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide

Product 1

HCID 86732112(4S,6S)-4-(5-amino-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amineYield 82.2%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
80 °C

Procedure

A microwave vial was charged with a solution of crude N-((4S,6S)-4-(5-amino-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (1k, 0.561 g, 1.357 mmol, Example 1 step 9) in MeOH (9 mL). 1,8-diazabicyclo[5.4.0]undec-7-ene (1.653 g, 10.86 mmol, Aldrich) was added and the vial was sealed. The reaction was heated to 80° C. in a microwave (Biotage Initiator) for a total of 135 minutes. The reaction was concentrated under reduced pressure. The crude material was taken up in EtOAc and washed with water (3×). The organic layer was extracted with 1N HCl (two times). The acidic aqueous layer was washed with EtOAc (twice). The acidic aqueous layer was basified with 5N NaOH to pH=12 and back extracted with EtOAc (twice). The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to afford the crude title compound as a grey oil (0.345 g, 1.116 mmol, 82% crude yield) which was used in the next step without further purification. MS m/z=310.0 [M+H]+. Calculated for C12H12F5N3O: 309.235

Workup

  1. customthe vial was sealed
  2. concentrationThe reaction was concentrated under reduced pressure
  3. washwashed with water (3×)
  4. extractionThe organic layer was extracted with 1N HCl (two times)
  5. washThe acidic aqueous layer was washed with EtOAc (twice)
  6. extractionback extracted with EtOAc (twice)
  7. washThe organic layer was washed with brine
  8. dry with materialdried over magnesium sulfate
  9. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-790a91527772427bac7008ed9d14553b
Source dataset
uspto-grants-2016_03
Patent number
US09296734B2

Reaction notes

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