Cesium carbonate → 5-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)nicotinonitrile

HRID 930320Notes

Reaction equation

HRID 930320 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[C:22]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[N:28][CH:29]=1)#[N:23].C(=O)([O-])[O-].[Cs+].[Cs+].C(C1C=NC=C(B2OC(C)(C)C(C)(C)O2)C=1)#N>C1COCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:16])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([C:26]3[CH:27]=[N:28][CH:29]=[C:24]([CH:25]=3)[C:22]#[N:23])[CH:3]=[CH:4][C:5]=2[F:21])([CH2:19][F:20])[N:9]=1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 164142165-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrileHCID 450795765-Cyanopyridine-3-boronic acidHCID 86732143(4S,6S)-4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine

Product 1

HCID 867321495-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)nicotinonitrileYield 65.9%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)Catalyst2×HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
80 °C

Procedure

In a microwave vial a mixture of (4S,6S)-4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (8a, 110 mg, 0.295 mmol), 5-cyano-3-pyridinyl boronic acid (43.6 mg, 0.295 mmol), and cesium carbonate (384 mg, 1.179 mmol) in THF (2.0 mL) and water (983 μL) was purged with argon for 5 min. Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (12.04 mg, 0.015 mmol) was added and the tube was sealed and the mixture was heated at 80° C. overnight. Additional 3-cyanopyridine-5-boronic acid pinacol ester (67.8 mg, 0.295 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (12.04 mg, 0.015 mmol) were added. The reaction mixture was stirred at 80° C. for another 6 h. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water and brine. The aqueous layer was back extracted with EtOAc (2×) and the combined organics was washed with brine, dried (Na2SO4) and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 0% EtOAc in hexane, to provide 5-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)nicotinonitrile (77 mg, 0.194 mmol, 65.9% yield) as off-white solid. MS m/z=397 [M]+. Calculated for C18H13F5N4O: 396.31.

Workup

  1. customwas purged with argon for 5 min
  2. customthe tube was sealed
  3. temperatureAfter cooling to room temperature
  4. customthe reaction mixture was partitioned between EtOAc and water and brine
  5. extractionThe aqueous layer was back extracted with EtOAc (2×)
  6. washthe combined organics was washed with brine
  7. dry with materialdried (Na2SO4)
  8. concentrationconcentrated
  9. customThe crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g)
  10. washeluting with a gradient of 0% to 0% EtOAc in hexane

Sources & evidence

ORD record
ord-9ae78750ce2943f89baa59d61f8379cc
Source dataset
uspto-grants-2016_03
Patent number
US09296734B2

Reaction notes

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