Cesium carbonate → HCID 86732170, compound

HRID 930350Notes

Reaction equation

HRID 930350 reaction equation
Br[C:2]1[N:7]=[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)[C:5]([F:21])=[CH:4][CH:3]=1.[C:22]([C:24]1[CH:25]=[CH:26][C:27]([C:30]([NH2:32])=[O:31])=[N:28][CH:29]=1)#[N:23].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[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[N:7]=[C:2]([NH:32][C:30](=[O:31])[C:27]3[CH:26]=[CH:25][C:24]([C:22]#[N:23])=[CH:29][N:28]=3)[CH:3]=[CH:4][C:5]=2[F:21])([CH2:19][F:20])[N:9]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 112750862-Pyridinecarboxamide,5-cyano-(9CI)HCID 86732169HCID 86732169, compound

Product 1

HCID 86732170HCID 86732170, compoundYield 28.7%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

To a resealable vial was added (4S,6S)-4-(6-bromo-3-fluoropyridin-2-yl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.200 g, 0.535 mmol), 5-cyanopicolinamide (0.118 g, 0.802 mmol), 1,4-dioxane (4 mL), and cesium carbonate (Strem Chemicals; 0.435 g, 1.337 mmol). The reaction vessel was carefully evacuated and backfilled with N2. This was repeated twice. To the solution was added tris(dibenzylideneacetone)dipalladium (0) (Aldrich; 0.049 g, 0.053 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Aldrich; 0.062 g, 0.107 mmol). The reaction vessel was carefully evacuated and backfilled with N2. This was repeated twice. The solution was stirred and heated at 100° C. for 3 h. The reaction mixture was allowed to cool to rt and poured into sat NaHCO3 (50 mL) and extracted with EtOAc (2×100 mL). The combined extracts were washed with water (100 mL) and brine (50 mL) and then dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (Gradient; 0.0 to 10% MeOH/CH2Cl2, Silicycle HP column, 40 g) followed by further purification by reverse phase preparative-HPLC afforded N-(6-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-5-cyanopicolinamide (0.0675 g, 0.153 mmol, 28.7% yield) as a white solid. MS m/z=440.9 [M+H]+. Calculated for C18H13F5N6O2: 440.1.

Workup

  1. customThe reaction vessel was carefully evacuated
  2. customThe reaction vessel was carefully evacuated
  3. temperatureto cool to rt
  4. additionpoured
  5. extractionextracted with EtOAc (2×100 mL)
  6. washThe combined extracts were washed with water (100 mL) and brine (50 mL)
  7. dry with materialdried (Na2SO4)
  8. concentrationconcentrated onto silica
  9. customPurification by silica gel chromatography (Gradient; 0.0 to 10% MeOH/CH2Cl2, Silicycle HP column, 40 g)
  10. customfollowed by further purification by reverse phase

Sources & evidence

ORD record
ord-084d5a3c86d64deb990d239d4c20e1b5
Source dataset
uspto-grants-2016_03
Patent number
US09296734B2

Reaction notes

Loading…