Cesium carbonate → [(S)-1-(7-Cyclopropyl-6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)ethyl]-[9-(tetrahydro-pyran-2-yl)-9H-purin-6-yl]amine

HRID 243058Notes

Reaction equation

HRID 243058 reaction equation
Br[C:2]1[C:7]2[N:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:9]([C@@H:11]([NH:13][C:14]3[N:22]=[CH:21][N:20]=[C:19]4[C:15]=3[N:16]=[CH:17][N:18]4[CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:35].[CH:36]1(B(O)O)[CH2:38][CH2:37]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[CH:36]1([C:2]2[C:7]3[N:8]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[C:9]([C@@H:11]([NH:13][C:14]4[N:22]=[CH:21][N:20]=[C:19]5[C:15]=4[N:16]=[CH:17][N:18]5[CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[CH3:12])=[N:10][C:6]=3[CH:5]=[CH:4][C:3]=2[F:35])[CH2:38][CH2:37]1

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 2760897Cyclopropylboronic acidHCID 68179439[(S)-1-(7-bromo-6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)ethyl]-[9-(tetrahydro-pyran-2-yl)-9H-purin-6-yl]amine

Product 1

HCID 68158234[(S)-1-(7-Cyclopropyl-6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)ethyl]-[9-(tetrahydro-pyran-2-yl)-9H-purin-6-yl]amineYield 24.2%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Procedure

To a solution of [(S)-1-(7-bromo-6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)ethyl]-[9-(tetrahydro-pyran-2-yl)-9H-purin-6-yl]amine (267 mg, 0.49 mmol) in dioxane (10 mL) and water (0.5 mL) was added cyclopropylboronic acid (64 mg, 0.75 mmol), cesium carbonate (242 mg, 0.75 mmol) and tetrakis(triphenylphosphine)palladium (0) (57 mg, 0.05 mmol) and the reaction mixture degassed by bubbling argon through the mixture whilst under sonication. The reaction mixture was heated at reflux for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to preparative HPLC (C18 Phenomenex column, 10-90% MeCN in water 0.1% formic acid, 25 min gradient) to yield the title compound as a white solid (59 mg, 24%). LCMS (Method C): RT=2.98 min, [M+H]+=499.

Workup

  1. customthe reaction mixture degassed
  2. customby bubbling argon through the mixture
  3. customwhilst under sonication
  4. temperatureThe reaction mixture was heated
  5. temperatureat reflux for 16 h
  6. additionThe reaction mixture was diluted with water
  7. extractionextracted with EtOAc (3×20 mL)
  8. washThe combined organic extracts were washed with brine
  9. dry with materialdried (MgSO4)
  10. concentrationconcentrated in vacuo
  11. customC18 Phenomenex column, 10-90% MeCN in water 0.1% formic acid, 25 min gradient

Sources & evidence

ORD record
ord-64cad1f038a54c93ba26d545b139cf3d
Source dataset
uspto-grants-2014_02
Patent number
US08653089B2

Reaction notes

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