Cesium carbonate → HCID 86732267, compound

HRID 930428Notes

Reaction equation

HRID 930428 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C@:9]1([CH2:28][F:29])[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[O:12][C:11]([NH:19]C(=O)C2C=CC=CC=2)=[N:10]1.[Cl:30][C:31]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:34]=[C:33](Cl)[N:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Cl:30][C:31]1[N:32]=[C:33]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C@:9]3([CH2:28][F:29])[CH2:14][C@@H:13]([C:15]([F:17])([F:16])[F:18])[O:12][C:11]([NH2:19])=[N:10]3)[CH:4]=2)[CH:34]=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:36]=1

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 113220482,6-dichloro-4-phenyl-pyridineHCID 86732146HCID 86732146, compound

Product 1

HCID 86732267HCID 86732267, compoundYield 2.96%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
100 °C

Procedure

In round-bottomed flask were added N-((4S,6S)-4-(2-fluoro-5-hydroxyphenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (225 mg, 0.543 mmol), 2,6-dichloro-4-phenylpyridine (146 mg, 0.652 mmol), cesium carbonate (230 mg, 0.706 mmol) in DMSO (1358 μl). The flask was heated in 100° C. oil bath for 7 h. After cooling to RT, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was back extracted with EtOAc (2×) and the combined organics was 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 50% EtOAc in hexane, followed by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 70% over 15 min, then neutralized with saturated NaHCO3 and extracted with DCM, to provide (4S,6S)-4-(5-((6-chloro-4-phenylpyridin-2-yl)oxy)-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (8 mg, 0.016 mmol, 2.96% yield) as a off-white solid.

Workup

  1. temperatureAfter cooling to RT
  2. customthe reaction mixture was partitioned between EtOAc and water
  3. extractionThe aqueous layer was back extracted with EtOAc (2×)
  4. dry with materialthe combined organics was dried (Na2SO4)
  5. concentrationconcentrated
  6. customThe crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g)
  7. washeluting with a gradient of 0% to 50% EtOAc in hexane
  8. customover 15 min
  9. extractionextracted with DCM

Sources & evidence

ORD record
ord-ba4375f8cd5d472c88a3263b4a5d8c7c
Source dataset
uspto-grants-2016_03
Patent number
US09296734B2

Reaction notes

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