Dimethylformamide → (S)-2-amino-4'-fluoro-7'-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9'-xanthen]-2'-ol

HRID 335727Notes

Reaction equation

HRID 335727 reaction equation
[NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:22]=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](Br)=[CH:9][CH:10]=1.[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1.CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:22]=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:27]2[CH:28]=[N:23][CH:24]=[N:25][CH:26]=2)=[CH:9][CH:10]=1

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 10340Sodium CarbonateHCID 2795193(Pyrimidin-5-yl)boronic acidHCID 58466133(S)-2-amino-7'-bromo-4'-fluoro-5H-spiro[oxazole-4,9'-xanthen]-2'-ol

Product 1

HCID 67241663(S)-2-amino-4'-fluoro-7'-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9'-xanthen]-2'-ol

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
85 °C

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. temperatureThe mixture was cooled to RT
  2. stirringstirring
  3. waitwas continued for 10 min
  4. filtrationThe precipitate was filtered out
  5. washwashed with water (3×5 mL), 1:1 i-PrOH/water
  6. customto remove color
  7. customdried in vacuo

Sources & evidence

ORD record
ord-01a4e06ef77f439da189245cdbc5781e
Source dataset
uspto-grants-2014_11
Patent number
US08883782B2

Reaction notes

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