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

HRID 600426Notes

Reaction equation

HRID 600426 reaction equation
[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:22])[N:8]2[C@H:11]2[C:20]3[C:15](=[C:16]([F:21])[CH:17]=[CH:18][CH:19]=3)[O:14][CH2:13][CH2:12]2)=[C:4]([Cl:23])[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]([F: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]>[Cl:23][C:4]1[N:3]=[C:2]([NH:1][C:77]2[CH:82]=[C:81]([F:83])[CH:80]=[CH:79][C:78]=2[N+:84]([O-:86])=[O:85])[N:10]=[C:9]2[C:5]=1[NH:6][C:7](=[O:22])[N:8]2[C@H:11]1[C:20]2[C:15](=[C:16]([F:21])[CH:17]=[CH:18][CH:19]=2)[O:14][CH2:13][CH2:12]1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 27569932-Bromo-4-fluoro-1-nitrobenzeneHCID 57612682(R)-2-amino-6-chloro-9-(8-fluorochroman-4-yl)-7H-purin-8(9H)-one

Product 1

HCID 57612627(R)-6-chloro-2-(5-fluoro-2-nitrophenylamino)-9-(8-fluorochroman-4-yl)-7H-purin-8(9H)-oneYield 46%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Procedure

To an oven-dried vial was added (R)-2-amino-6-chloro-9-(8-fluorochroman-4-yl)-7H-purin-8(9H)-one (152 mg, 0.45 mmol, 1 equiv.) in anhydrous toluene (2.5 mL), followed by freshly grounded cesium carbonate (207 mg, 0.64 mmol, 1.4 equiv.) with stirring at room temperature under Ar. After 10 min, Pd(OAc)2 (30.3 mg, 0.045 mmol, 0.1 equiv.), racemic BINAP (42 mg, 0.067 mmol, 0.15 equiv.) and 1-bromo-5-fluoro-2-nitrobenzene (130 mg, 0.59 mmol, 1.3 equiv.) were added as solids. The vial was purged with Ar for 3 min, then closed and heated at 80° C. for three days. The reaction mixture was cooled to room temperature, then poured into saturated aqueous NH4Cl (10 mL). To this mixture, saturated aqueous Na2EDTA (10 mL) was added and the mixture was stirred for 10 min. Then the reaction mixture was extracted with ethyl acetate (4×20 mL), the collected organic layers were washed with brine, dried (anhydrous Na2SO4) and the solvent evaporated in vacuo. Column chromatography of the residue on silica gel (gradual elution with 1% methanol in 4/2/1 hexane/methylene chloride/ethyl acetate to 2% methanol in 4/2/1 hexane/methylene chloride/ethyl acetate) afforded, after evaporation and drying, the desired product as an orange solid (76 mg, 46% yield based on 78% conversion), along with 33 mg of recovered starting material. 1H NMR (300 MHz, CDCl3) δ, ppm: 10.64 (s, 1H), 8.58 (s, 1H), 8.29-8.16 (m, 2H), 7.02-6.95 (m, 1H), 6.74-6.60 (m, 2H), 5.88-5.82 (m, 1H), 4.66-4.62 (m, 1H), 4.38 (app t, J=11.0 Hz, 1H), 4.38-4.28 (br m, 1H, overlapping with 4.38 ppm), 2.96-2.92 (m, 1H), 2.26-2.23 (m, 1H); MS (EI) m/z 475.2 (MH)+.

Workup

  1. customThe vial was purged with Ar for 3 min
  2. customclosed
  3. temperatureheated at 80° C. for three days
  4. temperatureThe reaction mixture was cooled to room temperature
  5. additionpoured into saturated aqueous NH4Cl (10 mL)
  6. additionTo this mixture, saturated aqueous Na2EDTA (10 mL) was added
  7. stirringthe mixture was stirred for 10 min
  8. extractionThen the reaction mixture was extracted with ethyl acetate (4×20 mL)
  9. washthe collected organic layers were washed with brine
  10. dry with materialdried (anhydrous Na2SO4)
  11. customthe solvent evaporated in vacuo
  12. customColumn chromatography of the residue on silica gel (gradual elution with 1% methanol in 4/2/1 hexane/methylene chloride/ethyl acetate to 2% methanol in 4/2/1 hexane/methylene chloride/ethyl acetate) afforded
  13. customafter evaporation
  14. customdrying

Sources & evidence

ORD record
ord-ba6646c13fd54d1fabb54f9007447e30
Source dataset
uspto-grants-2011_03
Patent number
US07902187B2

Reaction notes

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