Nitrogen → N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(4-pyridinyl)-1H-indazole-4-carboxamide

HRID 1476484Notes

Reaction equation

HRID 1476484 reaction equation
Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N#N>CO.C(Cl)(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.ClCCl.CCOC(C)=O.O.O1CCOCC1>[NH3:7].[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=[C:2]([C:30]2[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=2)[CH:3]=1)=[O:15]

Participants

13

Reactant 4

HCID 947NitrogenHCID 62657Potassium Phosphate, TribasicHCID 2734379(Pyridin-4-yl)boronic acidHCID 545964906-bromo-N-((1,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1-isopropyl-1H-indazole-4-carboxamide

Product 2

HCID 222AmmoniaHCID 67466071N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(4-pyridinyl)-1H-indazole-4-carboxamideYield 147.1%

Reagents, catalysts & solvents 7

HCID 178418807HCID 178418807, compoundCatalystHCID 887MethanolSolventHCID 962WaterSolventHCID 6212ChloroformSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

To a mixture of 6-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indazole-4-carboxamide (0.15 g, 0.359 mmol), 4-pyridinylboronic acid (0.088 g, 0.647 mmol) and potassium phosphate (tribasic) (0.229 g, 1.078 mmol) was added 1,4-dioxane (3 mL) and water (0.75 mL). The suspension was degassed with N2 for 10 min, at which time PdCl2(dppf)-CH2Cl2 (0.044 g, 0.054 mmol) was added and the sealed reaction heated at 100° C. overnight (reaction got very dark). Diluted reaction with EtOAc and filtered through Celite, washing with EtOAc and concentrated in vacuo to a residue that was dissolved in a minimum amount of DCM. Purification by silica gel chromatography (12 gram Isco GOLD silica column; Gradient B: 5-90%; A: dichloromethane, B: 10% (2 M ammonia in methanol) in chloroform) gave N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(4-pyridinyl)-1H-indazole-4-carboxamide (112 mg, 0.264 mmol, 73.5% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51 (d, J=6.57 Hz, 6H) 2.12 (s, 3H) 2.22 (s, 3H) 4.40 (d, J=4.80 Hz, 2H) 5.15-5.27 (m, 1H) 5.89 (s, 1H) 7.90-8.00 (m, 3H) 8.34 (s, 1H) 8.43 (s, 1H) 8.65-8.75 (m, 3H) 11.55 (s, 1H). MS (ES) [M+H]+ 416.1.

Workup

  1. additionwas added
  2. customthe sealed reaction
  3. custom(reaction got very dark)
  4. additionDiluted
  5. filtrationfiltered through Celite
  6. washwashing with EtOAc
  7. concentrationconcentrated in vacuo to a residue that
  8. dissolutionwas dissolved in a minimum amount of DCM
  9. customPurification by silica gel chromatography (12 gram Isco GOLD silica column

Sources & evidence

ORD record
ord-31bd20453b8c4e079139f9d968ee1bd5
Source dataset
uspto-grants-2015_04
Patent number
US09018382B2

Reaction notes

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