Cesium carbonate → (S)-4'-fluoro-2'-(2-fluoro-2-methylpropoxy)-7'-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9'-xanthen]-2-amine

HRID 335728Notes

Reaction equation

HRID 335728 reaction equation
[NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:27]=1)[C:18]1[CH:17]=[C:16]([OH:19])[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)=[CH:9][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:40][C:41]([F:44])([CH3:43])[CH3:42])(=O)=O>CN(C=O)C>[F:20][C:14]1[C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:21]4[CH:22]=[N:23][CH:24]=[N:25][CH:26]=4)=[CH:9][CH:10]=3)[C@@:5]3([CH2:4][O:3][C:2]([NH2:1])=[N:27]3)[C:18]=2[CH:17]=[C:16]([O:19][CH2:40][C:41]([F:44])([CH3:43])[CH3:42])[CH:15]=1

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 121655342-Fluoro-2-methylpropyl trifluoromethanesulfonateHCID 67241663(S)-2-amino-4'-fluoro-7'-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9'-xanthen]-2'-ol

Product 1

HCID 45254324(S)-4'-fluoro-2'-(2-fluoro-2-methylpropoxy)-7'-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9'-xanthen]-2-amine

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A 25 ml RBF was charged with (S)-2-amino-7′-bromo-4′-fluoro-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (629 mg, 1.723 mmol), tetrakis(triphenylphosphine)palladium (199 mg, 0.172 mmol), and pyrimidin-5-ylboronic acid (320 mg, 2.58 mmol). DMF (8613 μL) and sodium carbonate (2M solution) (2584 μL, 5.17 mmol) were added and the mixture was stirred at 85° C. for 2.5 hrs. The mixture was cooled to RT, water (˜5 ml) was added and stirring was continued for 10 min. The precipitate was filtered out, washed with water (3×5 mL), 1:1 i-PrOH/water to remove color and dried in vacuo to afford (S)-2-amino-4′-fluoro-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol as yellow solid. Step 2: A vial was charged with (S)-2-amino-4′-fluoro-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (61.0 mg, 0.167 mmol), cesium carbonate (82 mg, 0.251 mmol), and DMF (670 μL). The resulting mixture was stirred vigorously for 10 min, then the vial was placed in large ice-bath for 10 min and 2-fluoro-2-methylpropyl trifluoromethanesulfonate (33.3 μL, 0.201 mmol) was added dropwise. The ice bath was removed after 5 minutes and the mixture was stirred at RT for 6 hours before being diluted with water (10 mL) and extracted with EtOAc (3×5 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was chromatographed on a 12 g Redi-Sep column, eluting with 5-60% gradient of DCM/MeOH/NH4OH (90:10:1) in DCM to give (S)-4′-fluoro-2′-(2-fluoro-2-methylpropoxy)-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as an off-white solid.

Workup

  1. customfor 10 min
  2. customThe ice bath was removed after 5 minutes
  3. stirringthe mixture was stirred at RT for 6 hours
  4. additionbefore being diluted with water (10 mL)
  5. extractionextracted with EtOAc (3×5 mL)
  6. dry with materialThe combined organic extracts were dried over sodium sulfate
  7. filtrationfiltered
  8. customevaporated
  9. customThe residue was chromatographed on a 12 g Redi-Sep column
  10. washeluting with 5-60% gradient of DCM/MeOH/NH4OH (90:10:1) in DCM

Sources & evidence

ORD record
ord-8141ee512a8640a1a405a9a00d486ade
Source dataset
uspto-grants-2014_11
Patent number
US08883782B2

Reaction notes

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