Potassium Phosphate, Tribasic → HCID 89995501, compound

HRID 1487333Notes

Reaction equation

HRID 1487333 reaction equation
Br[C:2]1[N:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH2:16][F:17])[CH2:14][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12]3)=[C:8]([C:25](=[O:27])[NH2:26])[CH:7]=[N:6][N:5]2[CH:28]=1.[CH2:29]([N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1)[CH3:30].[O-]P([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:25]([C:8]1[CH:7]=[N:6][N:5]2[CH:28]=[C:2]([C:34]3[CH:33]=[N:32][N:31]([CH2:29][CH3:30])[CH:35]=3)[N:3]=[C:4]2[C:9]=1[NH:10][C@H:11]1[C@@H:15]([CH2:16][F:17])[CH2:14][N:13]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:12]1)(=[O:27])[NH2:26]

Participants

6

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 113790451-Ethyl-1H-pyrazole-4-boronic acid, pinacol esterHCID 89995574HCID 89995574, compound

Product 1

HCID 89995501HCID 89995501, compoundYield 65.4%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
100 °C

Procedure

A solution of (3S,4S)-tert-butyl 3-((2-bromo-7-carbamoylimidazo[1,2-b]pyridazin-8-yl)amino)-4-(fluoromethyl)pyrrolidine-1-carboxylate (22.2 mg, 0.049 mmol), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (21.56 mg, 0.097 mmol), PdCl2(dppf) CH2Cl2 Adduct (1:1) (3.99 mg, 4.85 μmol) in dioxane (0.5 ml) and 2M aq K3PO4 (0.073 ml, 0.146 mmol) in dioxane (0.5 ml) in a reaction vial was purged with N2 for 2 min. The reaction mixture was sealed and heated at 100° C. for 120 min. The reaction mixture was partitioned between EtOAc and water. The organic phase was washed with brine, filtered through CELITE®, dried (Na2SO4) and concentrated. The crude product was purified by flash column (ISCO 12 g-column, 20-80% EtOAc/hexane over 15 min) to afford (3S,4S)-tert-butyl 3-((7-carbamoyl-2-(1-ethyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-8-yl)amino)-4-(fluoromethyl)pyrrolidine-1-carboxylate (15 mg, 0.032 mmol, 65.4% yield) as a white solid. ESI-MS (Method A): m/z 473.4 ([M+H]+).

Workup

  1. customvial was purged with N2 for 2 min
  2. customThe reaction mixture was sealed
  3. customThe reaction mixture was partitioned between EtOAc and water
  4. washThe organic phase was washed with brine
  5. filtrationfiltered through CELITE®
  6. dry with materialdried (Na2SO4)
  7. concentrationconcentrated
  8. customThe crude product was purified by flash column (ISCO 12 g-column, 20-80% EtOAc/hexane over 15 min)

Sources & evidence

ORD record
ord-7f9327dba12d454aa7ded5e7a5af9ab7
Source dataset
uspto-grants-2016_08
Patent number
US09428511B2

Reaction notes

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