Potassium Phosphate, Tribasic → 4-(((3R,4R)-3-ethyl-1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl)amino)-6-(1-isopropyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide

HRID 877755Notes

Reaction equation

HRID 877755 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:22])[C:18]([OH:21])([CH3:20])[CH3:19])[CH2:13][C@H:12]3[CH2:23][CH3:24])=[C:8]([C:25]([NH2:27])=[O:26])[CH:7]=[N:6][N:5]2[CH:28]=1.[CH:29]([N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1)([CH3:31])[CH3:30].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>[CH2:23]([C@H:12]1[C@H:11]([NH:10][C:9]2[C:4]3[N:5]([CH:28]=[C:2]([C:35]4[CH:34]=[N:33][N:32]([CH:29]([CH3:31])[CH3:30])[CH:36]=4)[CH:3]=3)[N:6]=[CH:7][C:8]=2[C:25]([NH2:27])=[O:26])[CH2:16][CH2:15][N:14]([C:17](=[O:22])[C:18]([OH:21])([CH3:20])[CH3:19])[CH2:13]1)[CH3:24]

Participants

6

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 467380211-(Propan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 682913536-bromo-4-(((3R,4R)-3-ethyl-1-(2-hydroxy-2-methylpropanoyl)-piperidin-4-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide

Product 1

HCID 682916574-(((3R,4R)-3-ethyl-1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl)amino)-6-(1-isopropyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamideYield 68.6%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

To a vial charged with 6-bromo-4-(((3R,4R)-3-ethyl-1-(2-hydroxy-2-methylpropanoyl)-piperidin-4-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (20 mg, 0.044 mmol), 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (20.88 mg, 0.088 mmol), and PdCl2(dppf)-CH2Cl2 Adduct (3.61 mg, 4.42 μmol) were added 1,4-dioxane (295 μl) and a 2M solution of potassium phosphate (66.3 μl, 0.133 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 with methanol (10 ml), filtered, and concentrated under reduced pressure. The crude product was purified via preparative HPLC (Column: Waters XBridge C18, 19×200 mm, 5-μm). The collected fractions were combined and dried via centrifugal evaporation, yielding 4-(((3R,4R)-3-ethyl-1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl)amino)-6-(1-isopropyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (14.6 mg, 0.030 mmol, 68.6% yield) as a white solid. 1H NMR (500 MHz, 1:1 Chloroform-d/Methanol-d4) δ 8.10 (s, 1H), 7.83 (s, 1H), 7.75-7.72 (m, 2H), 6.92 (d, J=1.5 Hz, 1H), 4.65-4.50 (m, 2H), 4.32 (s, 2H), 4.15 (br. s., 1H), 2.97 (d, J=12.4 Hz, 1H), 2.36 (d, J=11.4 Hz, 1H), 1.79 (br. s., 1H), 1.70-1.61 (m, 2H), 1.57 (d, J=6.4 Hz, 6H), 1.49 (s, 6H), 1.41-1.25 (m, 1H), 1.01 (t, J=7.4 Hz, 3H). HPLC (Method F) Rt: 1.966 min. LCMS (Method K) m/z 482.29 ([M+H]+).

Workup

  1. customThe suspension was purged with nitrogen for 5 minutes
  2. customThe vial was sealed
  3. additionThe reaction was diluted with methanol (10 ml)
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe crude product was purified via preparative HPLC (Column: Waters XBridge C18, 19×200 mm, 5-μm)
  7. customdried via centrifugal evaporation

Sources & evidence

ORD record
ord-2299b8ff894e44cda24711e7754e85cb
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

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