Methanol → N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-6-chlorobenzo[d]oxazol-2-amine

HRID 930292Notes

Reaction equation

HRID 930292 reaction equation
[Cl:1][C:2]1[CH:38]=[CH:37][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([F:36])=[C:14]([C@:16]4([CH3:35])[CH2:21][C@@H:20]([C:22]([F:25])([F:24])[F:23])[O:19][C:18]([NH:26]C(=O)C5C=CC=CC=5)=[N:17]4)[CH:15]=3)[O:8][C:4]=2[CH:3]=1.C1CCN2C(=NCCC2)CC1.CO>[NH4+].[Cl-].CCOC(C)=O>[NH2:26][C:18]1[O:19][C@H:20]([C:22]([F:25])([F:24])[F:23])[CH2:21][C@:16]([C:14]2[CH:15]=[C:10]([NH:9][C:7]3[O:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:38]=[CH:37][C:5]=4[N:6]=3)[CH:11]=[CH:12][C:13]=2[F:36])([CH3:35])[N:17]=1

Participants

6

Reactant 3

HCID 887MethanolHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 86732122N-((4S,6S)-4-(5-((6-chlorobenzo[d]oxazol-2-yl)amino)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide

Product 1

HCID 86732124N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-6-chlorobenzo[d]oxazol-2-amineYield 8%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 25517Ammonium ChlorideSolvent

Conditions

Temperature
65 °C

Procedure

A mixture of N-((4S,6S)-4-(5-((6-chlorobenzo[d]oxazol-2-yl)amino)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (0.200 g, 0.366 mmol), DBU (0.072 mL, 0.475 mmol) and MeOH (3 mL) was stirred at 65° C. After 4 h, the mixture was diluted with saturated NH4Cl and EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The crude was purified by silica gel chromatography: 0-100% in 15 min, then 100% EtOAc-hexane. The product was obtained as a white solid (67.4 mg, 91% pure). The crude was further purified by reverse phase HPLC: 10-100% in 16 min, MeCN in water with 0.1% TFA. The combined fractions were neutralized with solid Na2CO3, and extracted with DCM three times. The organic phase was dried over Na2SO4 and concentrated in vacuo. The product was obtained as a white solid (12.7 mg, 8% yield). MS m/z=443 [M+H]+. Calculated for C19H15ClF4N4O2: 442.8.

Workup

  1. washThe organic layer was washed with water and brine
  2. dry with materialdried over Na2SO4
  3. concentrationconcentrated in vacuo
  4. customThe crude was purified by silica gel chromatography
  5. wait0-100% in 15 min
  6. customThe product was obtained as a white solid (67.4 mg, 91% pure)
  7. customThe crude was further purified by reverse phase HPLC
  8. wait10-100% in 16 min
  9. extractionextracted with DCM three times
  10. dry with materialThe organic phase was dried over Na2SO4
  11. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-03c016153e1e4681ae132702694758d6
Source dataset
uspto-grants-2016_03
Patent number
US09296734B2

Reaction notes

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