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

HRID 2074152Notes

Reaction equation

HRID 2074152 reaction equation
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:48]1[CH:53]=[C:52]([Cl:54])[CH:51]=[CH:50][C:49]=1[N+:55]([O-:57])=[O:56].[NH2:58][C:59]1[N:67]=[C:66]2[C:62]([NH:63][C:64](=[O:74])[N:65]2[CH:68]2[CH2:73][CH2:72][O:71][CH2:70][CH2:69]2)=[C:61]([Cl:75])[N:60]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:75][C:61]1[N:60]=[C:59]([NH:58][C:48]2[CH:53]=[C:52]([Cl:54])[CH:51]=[CH:50][C:49]=2[N+:55]([O-:57])=[O:56])[N:67]=[C:66]2[C:62]=1[NH:63][C:64](=[O:74])[N:65]2[CH:68]1[CH2:69][CH2:70][O:71][CH2:72][CH2:73]1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 98561242-Bromo-4-chloro-1-nitrobenzeneHCID 576126442-amino-6-chloro-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-one

Product 1

HCID 866229336-chloro-2-(5-chloro-2-nitrophenylamino)-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-oneYield 37%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent3×

Procedure

To an oven-dried 2-neck flask under Ar was added racemic BINAP (2.27 g, 3.64 mmol, 0.35 equiv.) followed by anhydrous toluene (20 mL) and Pd(OAc)2 (1.05 g, 1.56 mmol, 0.15 equiv.) and the mixture was stirred under Ar, at room temperature for 15 min. A deep yellow paste is formed. Then, 2-bromo-4-chloro-1 nitrobenzene (3.19 g, 13.52 mmol, 1.3 equiv.), 2-amino-6-chloro-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-one (2.80 g, 10.4 mmol, 1.0 equiv.) and cesium carbonate (5.08 g, 15.6 mmol, 1.5 equiv.) were added as solids, under Ar, followed by anhydrous toluene (22 mL), and the reaction mixture was stirred at room temperature for 10 min, then stirred at 100° C. for 17 h. The reaction mixture was cooled to room temperature, diluted with toluene (450 mL) and passed through Celite. The filtrate was concentrated in vacuo to give a dark brown residue. Flash chromatographic purification (silica gel, gradual elution with 1 to 5% methanol in methylene chloride), followed by recrystallization from hot ethyl acetate gave the desired product as a bright yellow solid (1.63 g, 37% yield) in high purity. 1H NMR (300 MHz, CDCl3+CD3OD) δ, ppm: 9.05 (s, 1H), 8.24 (d, 1H), 7.06 (d, 1H), 4.56-4.52 (m, 1H), 4.16 (dd, 2H), 3.58 (app t, 2H), 2.72 (tdd, 2H), 1.81 (br d, 2H); MS (EI) m/z 425.2 (MH)+.

Workup

  1. customA deep yellow paste is formed
  2. stirringthe reaction mixture was stirred at room temperature for 10 min
  3. stirringstirred at 100° C. for 17 h
  4. temperatureThe reaction mixture was cooled to room temperature
  5. concentrationThe filtrate was concentrated in vacuo
  6. customto give a dark brown residue
  7. customFlash chromatographic purification (silica gel, gradual elution with 1 to 5% methanol in methylene chloride)
  8. customfollowed by recrystallization from hot ethyl acetate

Sources & evidence

ORD record
ord-ca8a3970d0b1491eae5b9b70f15cb983
Source dataset
uspto-grants-2011_04
Patent number
US07919490B2

Reaction notes

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