Cesium carbonate → (S)-2-(2-amino-2'-(pyridin-3-yl)-5H-spiro[oxazole-4,9'-xanthene]-7'-yloxy)benzonitrile

HRID 335711Notes

Reaction equation

HRID 335711 reaction equation
NC1OC[C@:5]2([N:21]=1)[C:18]1C=C(Br)[CH:15]=[CH:14][C:13]=1OC1C2=CC(O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC1C=CC=CC=1C#N.[NH2:37][C:38]1[O:39][CH2:40][C@:41]2([N:65]=1)[C:54]1[CH:53]=[C:52](Br)[CH:51]=[CH:50][C:49]=1[O:48][C:47]1[C:42]2=[CH:43][C:44]([O:56][C:57]2[CH:64]=[CH:63][CH:62]=[CH:61][C:58]=2[C:59]#[N:60])=[CH:45][CH:46]=1.N1C=CC=C(B(O)O)C=1.C(=O)([O-])[O-].[K+].[K+]>O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1.CN(C=O)C>[NH2:37][C:38]1[O:39][CH2:40][C@:41]2([N:65]=1)[C:54]1[CH:53]=[C:52]([C:18]3[CH:5]=[N:21][CH:15]=[CH:14][CH:13]=3)[CH:51]=[CH:50][C:49]=1[O:48][C:47]1[C:42]2=[CH:43][C:44]([O:56][C:57]2[CH:64]=[CH:63][CH:62]=[CH:61][C:58]=2[C:59]#[N:60])=[CH:45][CH:46]=1

Participants

12

Reactant 6

HCID 10796Cesium carbonateHCID 11430Potassium CarbonateHCID 678552-FluorobenzonitrileHCID 27343783-Pyridinylboronic acidHCID 58466172(R)-2-amino-2'-bromo-5H-spiro[oxazole-4,9'-xanthen]-7'-olHCID 67242927(R)-2-(2-amino-2'-bromo-5H-spiro[oxazole-4,9'-xanthene]-7'-yloxy)benzonitrile

Product 1

HCID 58466265(S)-2-(2-amino-2'-(pyridin-3-yl)-5H-spiro[oxazole-4,9'-xanthene]-7'-yloxy)benzonitrile

Reagents, catalysts & solvents 5

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent2×

Conditions

Temperature
85 °C

Procedure

A vial was charged with (R)-2-amino-2′-bromo-5H-spiro[oxazole-4,9′-xanthen]-7′-ol (210 mg, 0.605 mmol), cesium carbonate (237 mg, 0.726 mmol), and DMF (4033 μL). The mixture was stirred for 15 min, then 2-fluorobenzonitrile (81 μL, 0.665 mmol) was added. The mixture was heated at 85° C. overnight. The reaction was diluted with water and EtOAc. The aqueous layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was chromatographed on a 40-g Redi-Sep column, eluting with 0-100% of a 90:10:1 mix of DCM/MeOH/NH4OH in DCM. The product isolated this way was impure, so the material was resubjected to chromatography on a 40-g Redi-Sep column, this time eluting with 0-100% EtOAc/Hexane. This gave (R)-2-(2-amino-2′-bromo-5H-spiro[oxazole-4,9′-xanthene]-7′-yloxy)benzonitrile as 94% pure by HPLC. It was a yellow solid after evaporation from DCM/hexane. Step 2: A vial was charged with (R)-2-(2-amino-2′-bromo-5H-spiro[oxazole-4,9′-xanthene]-7′-yloxy)benzonitrile (75 mg, 0.167 mmol), pyridin-3-ylboronic acid (51.4 mg, 0.418 mmol), tetrakis(triphenylphosphine)palladium(0) (9.67 mg, 8.37 μmol), THF (837 μL), and potassium carbonate (418 μL, 0.837 mmol) (as a 2.0 M aq. solution). The vial was sealed and heated to 100° C. in a shaker overnight. The mixture was diluted with EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc (2×). The combined organic extracts were evaporated, and the residue was chromatographed on a 25-g SNAP column, eluting with 0-80% of a 90:10:1 mix of DCM/MeOH/NH4OH in DCM to give (S)-2-(2-amino-2′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yloxy)benzonitrile as a pale-yellow solid.

Workup

  1. extractionThe aqueous layer was extracted with EtOAc (2×)
  2. dry with materialThe combined organic extracts were dried over sodium sulfate
  3. filtrationfiltered
  4. customevaporated
  5. customThe residue was chromatographed on a 40-g Redi-Sep column
  6. washeluting with 0-100% of a 90:10:1
  7. additionmix of DCM/MeOH/NH4OH in DCM
  8. customThe product isolated this way
  9. washthis time eluting with 0-100% EtOAc/Hexane
  10. customafter evaporation from DCM/hexane
  11. customThe vial was sealed
  12. temperatureheated to 100° C. in a shaker overnight
  13. customthe layers were separated
  14. extractionThe aqueous layer was extracted with EtOAc (2×)
  15. customThe combined organic extracts were evaporated
  16. customthe residue was chromatographed on a 25-g SNAP column
  17. washeluting with 0-80% of a 90:10:1
  18. additionmix of DCM/MeOH/NH4OH in DCM

Sources & evidence

ORD record
ord-ddc20d1a79a94f2a9a2333e2249fb21a
Source dataset
uspto-grants-2014_11
Patent number
US08883782B2

Reaction notes

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