Potassium Phosphate, Tribasic → (R)-tert-butyl 4-((7-carbamoyl-2-(1-ethyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-8-yl)amino)-3,3-dimethylpiperidine-1-carboxylate

HRID 1487329Notes

Reaction equation

HRID 1487329 reaction equation
Br[C:2]1[N:3]=[C:4]2[C:9]([NH:10][C@@H:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C:12]3([CH3:25])[CH3:24])=[C:8]([C:26](=[O:28])[NH2:27])[CH:7]=[N:6][N:5]2[CH:29]=1.[CH2:30]([N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1)[CH3:31].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[C:26]([C:8]1[CH:7]=[N:6][N:5]2[CH:29]=[C:2]([C:35]3[CH:34]=[N:33][N:32]([CH2:30][CH3:31])[CH:36]=3)[N:3]=[C:4]2[C:9]=1[NH:10][C@@H:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][C:12]1([CH3:24])[CH3:25])(=[O:28])[NH2:27]

Participants

6

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 113790451-Ethyl-1H-pyrazole-4-boronic acid, pinacol esterHCID 89995471(R)-tert-butyl 4-((2-bromo-7-carbamoylimidazo[1,2-b]pyridazin-8-yl)amino)-3,3-dimethylpiperidine-1-carboxylate

Product 1

HCID 89995480(R)-tert-butyl 4-((7-carbamoyl-2-(1-ethyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-8-yl)amino)-3,3-dimethylpiperidine-1-carboxylateYield 87.2%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

To a reaction vial charged with (R)-tert-butyl 4-((2-bromo-7-carbamoylimidazo[1,2-b]pyridazin-8-yl)amino)-3,3-dimethylpiperidine-1-carboxylate (69.1 mg, 0.148 mmol), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (65.7 mg, 0.296 mmol), and PdCl2(dppf)-CH2Cl2 Adduct (12.07 mg, 0.015 mmol) in dioxane (986 μl) was added potassium phosphate, dibasic (222 μl, 0.444 mmol). The suspension was purged with nitrogen for 5 minutes. The vial was sealed and heated at 100° C. for 2 hrs. The reaction was diluted methanol (10 ml), filtered, and concentrated. The resulting brown oil was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried with sodium sulfate, filtered, and concentrated to give an oil. The oil was purified via flash chromatography (ISCO silica gel column, 0-100% EtOAc/hexanes) to afford (R)-tert-butyl 4-((7-carbamoyl-2-(1-ethyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-8-yl)amino)-3,3-dimethylpiperidine-1-carboxylate (62.2 mg, 0.129 mmol, 87% yield) as a white solid. ESI-MS (analytical LCMS Method B): m/z 483.1 ([M+H]+). HPLC (analytical HPLC Method B) Rt: 3.345 min

Workup

  1. customTo a reaction
  2. customThe suspension was purged with nitrogen for 5 minutes
  3. customThe vial was sealed
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe resulting brown oil was partitioned between ethyl acetate and water
  7. washThe organic layer was washed with water and brine
  8. dry with materialdried with sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customto give an oil
  12. customThe oil was purified via flash chromatography (ISCO silica gel column, 0-100% EtOAc/hexanes)

Sources & evidence

ORD record
ord-5bf7db5ca6134cf8a49a399cb360eeb0
Source dataset
uspto-grants-2016_08
Patent number
US09428511B2

Reaction notes

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