Cesium carbonate → HCID 78321446, compound

HRID 930309Notes

Reaction equation

HRID 930309 reaction equation
CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:44]1[N:49]=[C:48]([C@:50]2([CH3:68])[CH2:55][C@@H:54]([C:56]([F:59])([F:58])[F:57])[O:53][C:52]([NH:60]C(=O)OC(C)(C)C)=[N:51]2)[C:47]([F:69])=[CH:46][CH:45]=1.[Cl:70][C:71]1[C:72]([C:81]([NH2:83])=[O:82])=[N:73][CH:74]=[C:75]([C:77]([F:80])([F:79])[F:78])[CH:76]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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]>[NH2:60][C:52]1[O:53][C@H:54]([C:56]([F:57])([F:58])[F:59])[CH2:55][C@:50]([C:48]2[N:49]=[C:44]([NH:83][C:81](=[O:82])[C:72]3[C:71]([Cl:70])=[CH:76][C:75]([C:77]([F:79])([F:78])[F:80])=[CH:74][N:73]=3)[CH:45]=[CH:46][C:47]=2[F:69])([CH3:68])[N:51]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 14787313-chloro-5-(trifluoromethyl)pyridine-2-carboxamide2×HCID 86732136HCID 86732136, compound

Product 1

HCID 78321446HCID 78321446, compoundYield 13.69%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
90 °C

Procedure

A sealable vial was charged with Pd2(dba)3 (Strem, 9.03 mg, 9.86 μmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (Strem, 22.83 mg, 0.039 mmol) and dioxane (0.5 mL). The reaction mixture was stirred under Nitrogen atmosphere for 10 min. A solution of tert-butyl ((4S,6S)-4-(6-bromo-3-fluoropyridin-2-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)carbamate (7i, 60 mg, 0.132 mmol) in 1,4-dioxane (1.3 mL), 3-chloro-5-(trifluoromethyl)picolinamide (intermediate 22, 42.8 mg, 0.191 mmol), and cesium carbonate (Aldrich, 107 mg, 0.329 mmol) were added. The vial was sealed flushed with nitrogen for 10 min and the reaction was heated to 90° C. for 3 h. The reaction mixture was cooled to RT and filtered through a pad of celite. The filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified 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 25 min. The product containing fractions were combined and neutralized with aqueous sodium bicarbonate solution. The free-based product was extracted with DCM. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure to afford the title compound (9 mg, 0.018 mmol, 13.69% yield) as white solid. MS m/z=500 [M]+. Calculated for C18H13ClF7N5O2: 499.7

Workup

  1. customThe vial was sealed
  2. customflushed with nitrogen for 10 min
  3. temperatureThe reaction mixture was cooled to RT
  4. filtrationfiltered through a pad of celite
  5. washThe filter cake was washed with EtOAc
  6. concentrationThe filtrate was concentrated under reduced pressure
  7. customthe residue was purified by reverse-phase preparative HPLC
  8. customover 25 min
  9. additionThe product containing fractions
  10. extractionThe free-based product was extracted with DCM
  11. dry with materialThe organic phase was dried over MgSO4
  12. customthe solvent was removed under reduced pressure

Sources & evidence

ORD record
ord-2dbe33dc53b841f6b1406c01e7842581
Source dataset
uspto-grants-2016_03
Patent number
US09296734B2

Reaction notes

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