Dimethylformamide → (S)-3-(2-amino-5'-fluoro-2'-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9'-xanthene]-7'-yloxy)-2,2-dimethylpropanenitrile

HRID 1970403Notes

Reaction equation

HRID 1970403 reaction equation
[NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:28]=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[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:9][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.FC(F)(F)S(O[CH2:46][C:47]([C:50]#[N:51])([CH3:49])[CH3:48])(=O)=O>O.CCOC(C)=O>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:28]=1)[C:6]1[CH:7]=[C:8]([C:21]3[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:9]=[CH:10][C:11]=1[O:12][C:13]1[C:18]2=[CH:17][C:16]([O:19][CH2:46][C:47]([CH3:49])([CH3:48])[C:50]#[N:51])=[CH:15][C:14]=1[F:20]

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 10796Cesium carbonateHCID 67242768(S)-2-amino-4'-fluoro-7'-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9'-xanthen]-2'-olHCID 866407352-Cyano-2-methylpropyl trifluoromethanesulfonate

Product 1

HCID 45254700(S)-3-(2-amino-5'-fluoro-2'-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9'-xanthene]-7'-yloxy)-2,2-dimethylpropanenitrile

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Procedure

A vial was charged with (S)-2-amino-4′-fluoro-7′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (45.0 mg, 0.118 mmol), cesium carbonate (57.7 mg, 0.177 mmol), and DMF (787 μL). The mixture was stirred vigorously for 15 min, then 2-cyano-2-methylpropyl trifluoromethanesulfonate (22.56 μL, 0.130 mmol) was added via syringe. The resulting mixture was stirred at room temperature for 19 hours before being diluted with water (10 mL) and EtOAc (10 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 12 g Redi-Sep column, eluting with 5-60% MeOH/DCM to give (S)-3-(2-amino-5′-fluoro-2′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yloxy)-2,2-dimethylpropanenitrile as an off-white solid. (MS: MH+=463).

Workup

  1. stirringThe resulting mixture was stirred at room temperature for 19 hours
  2. customThe layers were separated
  3. extractionthe aqueous layer was extracted with EtOAc (2×10 mL)
  4. dry with materialThe combined organic extracts were dried over sodium sulfate
  5. filtrationfiltered
  6. customevaporated
  7. customThe residue was purified by chromatography on a 12 g Redi-Sep column
  8. washeluting with 5-60% MeOH/DCM

Sources & evidence

ORD record
ord-eae17afd6b8c4b43865d143d10c30d2e
Source dataset
uspto-grants-2013_04
Patent number
US08426447B2

Reaction notes

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