Triethylamine → N-((4R,6S)-4-(6-bromo-3-fluoropyridin-2-yl)-4-(difluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide

HRID 930360Notes

Reaction equation

HRID 930360 reaction equation
[NH2:1][C@:2]([C:13]1[C:18]([F:19])=[CH:17][CH:16]=[C:15]([Br:20])[N:14]=1)([CH:10]([F:12])[F:11])[CH2:3][C@H:4]([OH:9])[C:5]([F:8])([F:7])[F:6].[C:21]([N:29]=[C:30]=S)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C1COCC1.O>[Br:20][C:15]1[N:14]=[C:13]([C@@:2]2([CH:10]([F:12])[F:11])[CH2:3][C@@H:4]([C:5]([F:6])([F:7])[F:8])[O:9][C:30]([NH:29][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:1]2)[C:18]([F:19])=[CH:17][CH:16]=1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 68284Benzoyl isothiocyanateHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 86732180(2S,4R)-4-amino-4-(6-bromo-3-fluoropyridin-2-yl)-1,1,1,5,5-pentafluoropentan-2-ol

Product 1

HCID 86732181N-((4R,6S)-4-(6-bromo-3-fluoropyridin-2-yl)-4-(difluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamideYield 74%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a 50-mL round-bottomed flask was added (2S,4R)-4-amino-4-(6-bromo-3-fluoropyridin-2-yl)-1,1,1,5,5-pentafluoropentan-2-ol (22 mg, 0.060 mmol) and benzoyl isothiocyanate (8.87 μl, 0.066 mmol) in THF (599 μl). The reaction mixture was stirred at RT for 16 h. To the reaction mixture was added triethylamine (10.00 μl, 0.072 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12.64 mg, 0.066 mmol). The mixture was heated at 75° C. for 1.5 h. The reaction mixture was allowed to cool to RT and was diluted with water and extracted with EtOAc. The organic extract was washed with satd NaCl (10 mL) and dried over MgSO4. The solution was filtered and concentrated in vacuo. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 30% EtOAc in hexane, to provide N-((4R,6S)-4-(6-bromo-3-fluoropyridin-2-yl)-4-(difluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (22 mg, 0.044 mmol, 74.0% yield) as off-white solid. MS m/z=496, 498 M+, Calculated for C18H12BrF6N3O2: 496.20.

Workup

  1. temperatureThe mixture was heated at 75° C. for 1.5 h
  2. temperatureto cool to RT
  3. extractionextracted with EtOAc
  4. extractionThe organic extract
  5. washwas washed with satd NaCl (10 mL)
  6. dry with materialdried over MgSO4
  7. filtrationThe solution was filtered
  8. concentrationconcentrated in vacuo
  9. customThe crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g)
  10. washeluting with a gradient of 0% to 30% EtOAc in hexane

Sources & evidence

ORD record
ord-e92d5511d59348fcb6c13fac521ff821
Source dataset
uspto-grants-2016_03
Patent number
US09296734B2

Reaction notes

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