Potassium Phosphate, Tribasic → (3R,4R)-tert-butyl 4-((3-carbamoyl-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-3-ethylpiperidine-1-carboxylate

HRID 877758Notes

Reaction equation

HRID 877758 reaction equation
Br[C:2]1[CH: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@H:12]3[CH2:24][CH3:25])=[C:8]([C:26](=[O:28])[NH2:27])[CH:7]=[N:6][N:5]2[CH:29]=1.[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[C:26]([C:8]1[CH:7]=[N:6][N:5]2[CH:29]=[C:2]([C:34]3[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=3)[CH: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]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13][C@H:12]1[CH2:24][CH3:25])(=[O:28])[NH2:27]

Participants

6

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 27739871-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 68291228HCID 68291228, compound

Product 1

HCID 68291150(3R,4R)-tert-butyl 4-((3-carbamoyl-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-3-ethylpiperidine-1-carboxylateYield 83%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

To a vial charged with (3R,4R)-tert-butyl 4-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-3-ethylpiperidine-1-carboxylate from Step 1 of Example 125 (349 mg, 0.748 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (467 mg, 2.245 mmol) and PdCl2(dppf)-CH2Cl2 Adduct (61.1 mg, 0.075 mmol) were added dioxane (5.0 ml) and a 2M solution of potassium phosphate (1.1 ml, 2.245 mmol). The suspension was purged with nitrogen for 5 minutes. The vial was sealed and heated at 100° C. for 1 hr. The reaction mixture was diluted with methanol (10 ml), filtered, and concentrated. The residue was partitioned between ethyl acetate (50 ml) and water. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified via medium pressure chromatography (silica gel column, EtOAc/hexanes eluent, 0-100% gradient elution) to yield (3R,4R)-tert-butyl 4-((3-carbamoyl-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-3-ethylpiperidine-1-carboxylate (288 mg, 0.618 mmol, 83% yield) as a white solid. LCMS (Method K) m/z 468.4 ([M+H]+).

Workup

  1. customThe suspension was purged with nitrogen for 5 minutes
  2. customThe vial was sealed
  3. additionThe reaction mixture was diluted with methanol (10 ml)
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe residue was partitioned between ethyl acetate (50 ml) and water
  7. washThe organic layer was washed with brine
  8. dry with materialdried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. customThe crude product was purified via medium pressure chromatography (silica gel column, EtOAc/hexanes eluent, 0-100% gradient elution)

Sources & evidence

ORD record
ord-8d55e352360a4cb29eae3b0930fea127
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

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