Sodium Carbonate → 3-((4S,6S)-2-benzamido-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluoro-N-((S)-1-methoxypropan-2-yl)benzamide

HRID 930410Notes

Reaction equation

HRID 930410 reaction equation
Br[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:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:9]2)[CH:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)[O:51][C:33]2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Na+].[Na+].[CH3:78][O:79][CH2:80][C@@H:81]([NH2:83])[CH3:82]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:19]([NH:18][C:10]1[O:11][C@H:12]([C:14]([F:16])([F:17])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=2[F:29])[C:33]([NH:83][C@@H:81]([CH3:82])[CH2:80][O:79][CH3:78])=[O:51])([CH2:27][F:28])[N:9]=1)(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1

Participants

7

Reactant 4

HCID 10340Sodium CarbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 70215362-Propanamine, 1-methoxy-, (2S)-HCID 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 867322493-((4S,6S)-2-benzamido-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluoro-N-((S)-1-methoxypropan-2-yl)benzamideYield 396.6%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Procedure

To a flask was added N-((4S,6S)-4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (0.248 g, 0.519 mmol), palladium acetate (5.25 mg, 0.023 mmol), xantphos (0.017 g, 0.029 mmol), and sodium carbonate (0.033 ml, 0.779 mmol) in toluene (1.039 mL). (s)-(+)-1-Methoxy-2-propylamine (0.082 ml, 0.779 mmol) was added. CO gas was bubbled through the reaction mixture for 10 min. The temperature was then brought to 80° C. for 3 h. Then the reaction was allowed to cool to room temperature. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with water, saturated NaHCO3 solution, brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP Ultra silica gel column (50 g), eluting with a gradient of 5-80% EtOAc in hexane, to provide 3-((4S,6S)-2-benzamido-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluoro-N-((S)-1-methoxypropan-2-yl)benzamide (0.0591 g, 0.115 mmol, 22.16% yield). MS m/z=514.0 [M+H]+. Calculated for C24H24F5N3O4: 513.17

Workup

  1. customCO gas was bubbled through the reaction mixture for 10 min
  2. additionThe reaction mixture was diluted with water
  3. extractionextracted with EtOAc
  4. extractionThe organic extract
  5. washwas washed with water, saturated NaHCO3 solution, brine
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customchromatographed through a Biotage SNAP Ultra silica gel column (50 g)
  10. washeluting with a gradient of 5-80% EtOAc in hexane

Sources & evidence

ORD record
ord-ee74984e90b94b98b12455d70ec6124e
Source dataset
uspto-grants-2016_03
Patent number
US09296734B2

Reaction notes

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