Trifluoroacetic acid → N-(2-methoxypyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-1H-pyrazolo[4,3-c]pyridin-3-amine

HRID 1046505Notes

Reaction equation

HRID 1046505 reaction equation
I[C:2]1[C:6]2[C:7]([O:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][CH:9]=[CH:10][C:5]=2[N:4](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:3]=1.[NH2:37][C:38]1[CH:43]=[CH:42][N:41]=[C:40]([O:44][CH3:45])[CH:39]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)Cl>[CH3:45][O:44][C:40]1[CH:39]=[C:38]([NH:37][C:2]2[C:6]3[C:7]([O:11][CH:12]4[CH2:13][CH2:14][O:15][CH2:16][CH2:17]4)=[N:8][CH:9]=[CH:10][C:5]=3[NH:4][N:3]=2)[CH:43]=[CH:42][N:41]=1

Participants

9

Reactant 6

HCID 6422Trifluoroacetic acidHCID 10796Cesium carbonateHCID 12052TriethylsilaneHCID 2808912-Methoxypyridin-4-amineHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 66826813HCID 66826813, compound

Product 1

HCID 66828979N-(2-methoxypyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-1H-pyrazolo[4,3-c]pyridin-3-amineYield 7.3%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6344DichloromethaneSolvent

Procedure

To a microwave tube was added 3-iodo-4-(tetrahydro-2H-pyran-4-yloxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine (260 mg, 0.44 mmol), 4-amino-2-methoxy-pyridine (66 mg, 0.53 mmol), cesium carbonate (0.29 g, 0.88 mmol), XPhos (21 mg, 0.044 mmol), and tris(dibenzylideneacetone)dipalladium (20 mg, 0.022 mmol). The tube was then flushed with nitrogen for 1 minute before the addition of 1,4-dioxane (2.5 mL). The tube was sealed and irradiated in the microwave at 140° C. for 35 minutes. The reaction mixture was filtered through Celite® and concentrated. The crude material was filtered through a silica gel column (EtOAc) and concentrated. To the residue was added DCM (3 mL), triethylsilane (0.1 mL, 0.63 mmol) and trifluoroacetic acid (0.50 mL, 6.5 mmol). The mixture was stirred at room temperature for 15 minutes before concentrated under vacuum. The crude material was purified by reverse phase HPLC to give the title compound (11 mg, 7.3% over 2 steps). LC-MS (Method G): m/z=342.1 [M+H]+, 2.94 min. 1H-NMR (400 MHz, DMSO): δ 12.78 (s, 1H), 8.26 (s, 1H), 7.90 (d, J=5.6, 1H), 7.81 (d, J=6.0, 1H), 6.99 (d, J=6.0, 1H), 6.90 (d, J=5.4, 1H), 6.86 (s, 1H), 5.39 (m, 1H), 3.80 (m, 5H), 3.50 (m, 2H), 1.99 (m, 2H), 1.76 (m, 2H).

Workup

  1. customThe tube was then flushed with nitrogen for 1 minute before the addition of 1,4-dioxane (2.5 mL)
  2. customThe tube was sealed
  3. customirradiated in the microwave at 140° C. for 35 minutes
  4. filtrationThe reaction mixture was filtered through Celite®
  5. concentrationconcentrated
  6. filtrationThe crude material was filtered through a silica gel column (EtOAc)
  7. concentrationconcentrated
  8. concentrationbefore concentrated under vacuum
  9. customThe crude material was purified by reverse phase HPLC

Sources & evidence

ORD record
ord-1ebb8381d0f74d7a983a46d28b5eaee8
Source dataset
uspto-grants-2013_10
Patent number
US08569281B2

Reaction notes

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