Cesium carbonate → 1-(6-(5-(6-isopropoxypyrazin-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-amine

HRID 1529261Notes

Reaction equation

HRID 1529261 reaction equation
C(=O)([O-])[O-].[Cs+].[Cs+].[CH:7]([O:10][C:11]1[CH:16]=[N:15][CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[N:12]=1)([CH3:9])[CH3:8].Br[C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32](C1CCCCO1)[N:31]=[C:30]2[C:42]1[N:47]=[C:46]([N:48]2[CH2:53][CH2:52][CH:51]([NH:54]C(=O)OC(C)(C)C)[CH2:50][CH2:49]2)[CH:45]=[N:44][CH:43]=1>[Cu]I.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:7]([O:10][C:11]1[N:12]=[C:13]([C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[NH:32][N:31]=[C:30]3[C:42]2[N:47]=[C:46]([N:48]3[CH2:49][CH2:50][CH:51]([NH2:54])[CH2:52][CH2:53]3)[CH:45]=[N:44][CH:43]=2)[CH:14]=[N:15][CH:16]=1)([CH3:8])[CH3:9]

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 457862332-Isopropoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazineHCID 67959723tert-butyl 1-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate2×

Product 1

HCID 679596291-(6-(5-(6-isopropoxypyrazin-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-amine

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 167845palladium(II) acetateCatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)Catalyst

Conditions

Temperature
80 °C

Procedure

A mixture of CuI (Aldrich, 26.6 mg, 0.27 mmol), cesium carbonate (Aldrich, 351 mg, 1.08 mmol), 1,1′-bis(diphenylphosphino)ferrocene (14.9 mg, 0.03 mmol), palladium(II) acetate (Strem Chemicals, 3.0 mg, 0.01 mmol), 2-isopropoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine (Combi-Phos, 142 mg, 0.54 mmol), and tert-butyl 1-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (compound 1e, 150 mg, 0.27 mmol) in a 5 mL conical microwave vial was sealed, evacuated and back-filled with N2 3×. DMF (2.7 mL) was added, and the reaction mixture was stirred at 80° C. for 16 h. The resulting reaction mixture was cooled to RT, filtered, and concentrated to dryness. The crude product was purified by HPLC (5 to 80% 0.1% TFA:Water:0.1% TFA:ACN over 25 min). The fractions were combined, washed with sat. aq. NaHCO3 and extracted with 20% IPA in chloroform. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to a tan oil. The oil was dissolved in MeOH/DCM before adding 6 N HCl in IPA and stirring at 80° C. for 2 h. The reaction mixture was concentrated under reduced pressure before resolubilizing with MeOH and passing through a MeOH washed plug of Si-propylsulfonic acid. The compound was released with 2M NH3 in MeOH (30 mL) to afford 1-(6-(5-(6-isopropoxypyrazin-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-amine as a dark tan solid. MS (ESI, pos. ion) m/z: 431 (M+1).

Workup

  1. customwas sealed
  2. customevacuated
  3. additionback-filled with N2 3×
  4. additionDMF (2.7 mL) was added
  5. customThe resulting reaction mixture
  6. temperaturewas cooled to RT
  7. filtrationfiltered
  8. concentrationconcentrated to dryness
  9. customThe crude product was purified by HPLC (5 to 80% 0.1% TFA:Water:0.1% TFA:ACN over 25 min)
  10. washwashed with sat. aq. NaHCO3
  11. extractionextracted with 20% IPA in chloroform
  12. dry with materialThe combined organics were dried over Na2SO4
  13. filtrationfiltered
  14. concentrationconcentrated under reduced pressure to a tan oil
  15. dissolutionThe oil was dissolved in MeOH/DCM
  16. additionbefore adding 6 N HCl in IPA
  17. stirringstirring at 80° C. for 2 h
  18. concentrationThe reaction mixture was concentrated under reduced pressure

Sources & evidence

ORD record
ord-0fdcc7d2316d4df6be21c40b0766f6d7
Source dataset
uspto-grants-2015_07
Patent number
US09090593B2

Reaction notes

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