Potassium Phosphate, Tribasic → HCID 68292325, compound

HRID 1507951Notes

Reaction equation

HRID 1507951 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]([CH3:19])[C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14])=[C:8]([C:20](=[O:22])[NH2:21])[CH:7]=[N:6][N:5]2[CH:23]=1.[CH3:24][O:25][C:26]1[N:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:20]([C:8]1[CH:7]=[N:6][N:5]2[CH:23]=[C:2]([C:29]3[CH:30]=[N:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)[CH:3]=[C:4]2[C:9]=1[NH:10][C@H:11]([CH3:19])[C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14])(=[O:22])[NH2:21]

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 2734368(6-Methoxypyridin-3-yl)boronic acidHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 68291276HCID 68291276, compound

Product 1

HCID 68292325HCID 68292325, compoundYield 66.2%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
135 °C

Procedure

A mixture of (R)-methyl 3-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-2,2-dimethylbutanoate (170 mg, 0.444 mmol) and (6-methoxypyridin-3-yl) boronic acid (102 mg, 0.665 mmol) were taken in 1,4-dioxane (5 mL) in a sealed tube. To this mixture were added 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (21.15 mg, 0.044 mmol) and palladium (II) acetate (4.98 mg, 0.022 mmol) followed by K3PO4 (2M solution) (0.554 mL, 1.109 mmol). The reaction mixture was degassed and heated to 135° C. for 1 h. After completion of the reaction, the reaction mixture was cooled, quenched with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine (60 mL), dried over anhyd. sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product as a brown liquid. The crude product was purified by flash chromatography over silica gel and eluted using 40% ethyl acetate in petroleum ether to give the title compound (125 mg, 0.293 mmol, 66.2% yield) as an off white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.24-1.25 (d, J=1.6 Hz, 6H), 1.28-1.3 (d, J=6.8 Hz, 3H), 3.57 (s, 3H), 3.89 (s, 3H), 4.65-4.69 (m, 1H), 6.87-6.89 (d, J=8.4 Hz, 1H), 7.28-7.29 (d, J=1.6 Hz, 1H), 8.12-8.15 (dd, J=2.4 Hz, J=2.8 Hz, 1H), 8.205-8.209 (d, J=1.6 Hz, 2H), 8.65-8.66 (d, J=2.4 Hz, 1H), 10.91-10.94 (d, J=10 Hz, 1H). [α]24.8=8.0 (c=0.1, MeOH).

Workup

  1. customThe reaction mixture was degassed
  2. customAfter completion of the reaction
  3. temperaturethe reaction mixture was cooled
  4. customquenched with water (50 mL)
  5. extractionextracted with ethyl acetate (3×50 mL)
  6. washThe combined organic layer was washed with brine (60 mL)
  7. customdried over anhyd
  8. filtrationsodium sulfate, filtered
  9. concentrationconcentrated under reduced pressure
  10. customto afford the crude product as a brown liquid
  11. customThe crude product was purified by flash chromatography over silica gel
  12. washeluted

Sources & evidence

ORD record
ord-f2a411ac648942cfbb5eeca621230b6b
Source dataset
uspto-grants-2015_12
Patent number
US09221826B2

Reaction notes

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