Potassium Phosphate, Tribasic → HCID 89995644, compound

HRID 1487322Notes

Reaction equation

HRID 1487322 reaction equation
Br[C:2]1[N:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH3:16])[CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)=[C:8]([C:24](=[O:26])[NH2:25])[CH:7]=[N:6][N:5]2[CH:27]=1.[CH3:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]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:24]([C:8]1[CH:7]=[N:6][N:5]2[CH:27]=[C:2]([C:32]3[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=3)[N:3]=[C:4]2[C:9]=1[NH:10][C@H:11]1[C@@H:15]([CH3:16])[CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1)(=[O:26])[NH2:25]

Participants

6

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 27739871-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 89995496HCID 89995496, compound

Product 1

HCID 89995644HCID 89995644, compound

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

To a reaction vial charged with (3S,4S)-tert-butyl 3-((2-bromo-7-carbamoylimidazo[1,2-b]pyridazin-8-yl)amino)-4-methylpyrrolidine-1-carboxylate (from Step 3 of Example 1, 300 mg, 0.683 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (426 mg, 2.049 mmol) and PdCl2(dppf)-CH2Cl2 Adduct (55.8 mg, 0.068 mmol) were added dioxane (4.553 ml) and potassium phosphate, tribasic (1024 μl, 2.049 mmol). The suspension was purged with nitrogen for 5 minutes. The vial was sealed and heated at 90° C. for 1 hr. The reaction mixture was diluted with methanol (10 ml), filtered, and concentrated under reduced pressure, yielding a dark oil. The oil was partitioned between ethyl acetate and water. The organic layer was washed with (sat.) sodium chloride, dried with sodium sulfate, filtered and concentrated under reduced pressure to give an oil. The crude oil was purified via flash chromatography (ISCO silica gel column, 0-10% DCM-MeOH eluents) to give (3S,4S)-tert-butyl 3-((7-carbamoyl-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-8-yl)amino)-4-methylpyrrolidine-1-carboxylate as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ 8.33 (s, 1H), 8.03-7.95 (m, 2H), 7.86 (s, 1H), 6.07-5.86 (m, 1H), 3.93 (s, 3H), 3.85-3.73 (m, 1H), 3.72-3.62 (m, 1H), 3.57-3.45 (m, 1H), 3.23-3.14 (m, 1H), 2.67 (d, J=4.8 Hz, 1H), 1.46 (d, J=13.0 Hz, 9H), 1.16-1.06 (m, 3H). ESI-MS (analytical LCMS Method B): m/z 441.3 ([M+H]+). HPLC (analytical HPLC Method B) Rt: 3.123 min.

Workup

  1. customTo a reaction
  2. customThe suspension was purged with nitrogen for 5 minutes
  3. customThe vial was sealed
  4. additionThe reaction mixture was diluted with methanol (10 ml)
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customyielding a dark oil
  8. customThe oil was partitioned between ethyl acetate and water
  9. washThe organic layer was washed with (sat.) sodium chloride
  10. dry with materialdried with sodium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated under reduced pressure
  13. customto give an oil
  14. customThe crude oil was purified via flash chromatography (ISCO silica gel column, 0-10% DCM-MeOH eluents)

Sources & evidence

ORD record
ord-6c6415f59aee4c79a33926526127843a
Source dataset
uspto-grants-2016_08
Patent number
US09428511B2

Reaction notes

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