Cesium carbonate → 6-chloro-2-(5-fluoro-2-nitrophenylamino)-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-one

HRID 600400Notes

Reaction equation

HRID 600400 reaction equation
[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:17])[N:8]2[CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:4]([Cl:18])[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:72]1[CH:77]=[C:76]([F:78])[CH:75]=[CH:74][C:73]=1[N+:79]([O-:81])=[O:80].CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:18][C:4]1[N:3]=[C:2]([NH:1][C:72]2[CH:77]=[C:76]([F:78])[CH:75]=[CH:74][C:73]=2[N+:79]([O-:81])=[O:80])[N:10]=[C:9]2[C:5]=1[NH:6][C:7](=[O:17])[N:8]2[CH:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1

Participants

8

Reactant 5

HCID 10796Cesium carbonateHCID 81531DiisopropylethylamineHCID 634876Binap, (A+-)-HCID 27569932-Bromo-4-fluoro-1-nitrobenzeneHCID 576126442-amino-6-chloro-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-one

Product 1

HCID 866229326-chloro-2-(5-fluoro-2-nitrophenylamino)-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-oneYield 60%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
80 °C

Procedure

To an oven-dried vial was added 2-amino-6-chloro-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-one (50 mg of HCl salt, 0.186 mmol, 1 equiv.) in anhydrous toluene (3 mL), then freshly grounded cesium carbonate (85 mg, 0.26 mmol, 1.4 equiv.) with stirring at room temperature under Ar. After 20 min, Pd(OAc)2 (12.5 mg, 0.019 mmol, 0.1 equiv.), racemic BINAP (17.3 mg, 0.028 mmol, 0.15 equiv.) and 1-bromo-5-fluoro-2-nitrobenzene (Oakwood) (53 mg, 0.24 mmol, 1.3 equiv.) were added as solids, followed by DIEA (50 μL, 1.5 equiv.). The vial was purged with Ar for 3 min, then closed and heated at 80° C. for 18 h. The reaction mixture was cooled to room temperature, diluted with 5% methanol in methylene chloride, filtered through a Nylon 0.45 μm filter, and the filter repeatedly washed with 5% methanol in methylene chloride. The filtrate was concentrated in vacuo and the resulting residue was purified using preparative TLC (silica gel, 4.25% methanol in methylene chloride) to give the desired product as a yellow solid (45.3 mg, 60% yield). 1H NMR (300 MHz, CDCl3) δ, ppm: 10.90 (s, 1H), 8.89 (dd, 1H), 8.45 (dd, 1H), 8.10 (br s, 1H), 6.92-6.83 (m, 1H), 4.75-4.60 (m, 1H), 4.28 (dd, 2H), 3.65 (app t, 2H), 2.82 (tdd, 2H), 1.90 (br d, 2H); MS (EI) m/z 409.1 (MH)+.

Workup

  1. customThe vial was purged with Ar for 3 min
  2. customclosed
  3. temperatureThe reaction mixture was cooled to room temperature
  4. additiondiluted with 5% methanol in methylene chloride
  5. filtrationfiltered through a Nylon 0.45 μm
  6. filtrationfilter
  7. filtrationthe filter repeatedly
  8. washwashed with 5% methanol in methylene chloride
  9. concentrationThe filtrate was concentrated in vacuo
  10. customthe resulting residue was purified

Sources & evidence

ORD record
ord-9990a27556b04299a1c62d2d52cfb8e1
Source dataset
uspto-grants-2011_03
Patent number
US07902187B2

Reaction notes

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