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

HRID 600408Notes

Reaction equation

HRID 600408 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]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[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:77]1[CH:82]=[C:81]([Cl:83])[CH:80]=[CH:79][C:78]=1[N+:84]([O-:86])=[O:85]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].CS(C)=O>[Cl:83][C:81]1[CH:80]=[CH:79][C:78]([N+:84]([O-:86])=[O:85])=[C:77]([NH:1][C:2]2[N:10]=[C:9]3[C:5]([NH:6][C:7](=[O:17])[N:8]3[CH:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)=[C:4]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:3]=2)[CH:82]=1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 98561242-Bromo-4-chloro-1-nitrobenzeneHCID 576126402-amino-6-(pyridin-4-yl)-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-one

Product 1

HCID 576127192-(5-chloro-2-nitrophenylamino)-6-(pyridin-4-yl)-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-oneYield 11%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 679Dimethyl SulfoxideSolventHCID 1140TolueneSolvent

Conditions

Temperature
170 °C

Procedure

To an oven-dried vial was added 2-amino-6-(pyridin-4-yl)-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-one (68 mg, 0.22 mmol, 1 equiv.) in anhydrous toluene (1 mL), then freshly grounded cesium carbonate (99.4 mg, 0.31 mmol, 1.4 equiv.) with stirring at room temperature under Ar. After 20 min, Pd(OAc)2 (15 mg, 0.02 mmol, 0.1 equiv.), racemic BINAP (20.5 mg, 0.03 mmol, 0.15 equiv.) and 1-bromo-5-chloro-2-nitrobenzene (WO 02/053545 A1) (67.6 mg, 0.29 mmol, 1.3 equiv.) were added as solids, followed by anhydrous DMSO (1 mL). The vial was purged with Ar for 3 min, then closed and heated in a microwave oven at 170° C. for 45 min. The reaction mixture was cooled to room temperature, diluted with ethyl acetate/methylene chloride, filtered through a Nylon 0.45 μm filter, and the filtrate was concentrated in vacuo. The resulting residue was purified using preparative TLC (silica gel, 7.5% methanol in methylene chloride) to give the desired product as a brown solid (11 mg, 11% yield). 1H NMR (300 MHz, CDCl3+CD3OD) δ, ppm: 9.13 (s, 1H), 8.63 (br m, 2H), 8.13 (d, J=8.9 Hz, 1H), 7.83 (br m, 2H), 6.91 (d, J=8.6 Hz, 1H), 4.70-4.50 (m, 1H), 4.10-4.03 (m, 2H), 3.51-3.43 (m, 2H), 2.68-2.65 (m, 2H), 1.71-1.66 (m, 2H); MS (EI) m/z 468.4 (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 ethyl acetate/methylene chloride
  5. filtrationfiltered through a Nylon 0.45 μm
  6. filtrationfilter
  7. concentrationthe filtrate was concentrated in vacuo
  8. customThe resulting residue was purified

Sources & evidence

ORD record
ord-877b7683e96445b8bf14ea08ad5ca9a7
Source dataset
uspto-grants-2011_03
Patent number
US07902187B2

Reaction notes

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