Potassium Phosphate, Tribasic → (2-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(5-(5-ethyl-1-methyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-3-yl)methyl Acetate

HRID 407676Notes

Reaction equation

HRID 407676 reaction equation
Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH2:16][CH3:17])[N:13]([CH3:18])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:19]([O:22][CH2:23][C:24]1[C:25]([N:33]2[N:42]=[CH:41][C:40]3[C:35](=[C:36]([F:47])[CH:37]=[C:38]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:39]=3)[C:34]2=[O:48])=[N:26][CH:27]=[CH:28][C:29]=1B(O)O)(=[O:21])[CH3:20].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>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].O.C(#N)C>[C:19]([O:22][CH2:23][C:24]1[C:25]([N:33]2[N:42]=[CH:41][C:40]3[C:35](=[C:36]([F:47])[CH:37]=[C:38]([C:43]([CH3:45])([CH3:44])[CH3:46])[CH:39]=3)[C:34]2=[O:48])=[N:26][CH:27]=[CH:28][C:29]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH2:16][CH3:17])[N:13]([CH3:18])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:21])[CH3:20]

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 517045Sodium AcetateHCID 866839433-(Acetoxymethyl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyridin-4-ylboronic AcidHCID 866839595-Bromo-3-(5-ethyl-1-methyl-1H-pyrazol-3-ylamino)-1-methylpyridin-2(1H)-one

Product 1

HCID 86683960(2-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(5-(5-ethyl-1-methyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-3-yl)methyl AcetateYield 25%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
100 °C

Procedure

A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 122b (310 mg, 1.0 mmol), 3-(acetoxymethyl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyridin-4-ylboronic acid 116c (1.24 g, 3.0 mmol), K3PO4 (424 mg, 2.0 mmol), sodium acetate (164 mg, 2.0 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (73 mg, 0.10 mmol), acetonitrile (10 mL), and water (0.5 mL). The system was subject to three cycles of vacuum/nitrogen flush and heated at 100° C. under N2 protection for 2.5 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with dichloromethane (50 mL) and water (50 mL). The aqueous layer was separated and extracted with dichloromethane (3×20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified with silica-gel column chromatography eluting with 60:1 dichloromethane/methanol to afford 122c (150 mg, 25%) as a yellow oil. MS-ESI: [M+H]+ 600.0

Workup

  1. customA 50-mL round-bottomed flask equipped with a reflux condenser
  2. customflush
  3. temperatureThe reaction mixture was cooled to room temperature
  4. concentrationconcentrated under reduced pressure
  5. additionThe residue was diluted with dichloromethane (50 mL) and water (50 mL)
  6. customThe aqueous layer was separated
  7. extractionextracted with dichloromethane (3×20 mL)
  8. dry with materialThe combined organic layer was dried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. customThe dark residue was purified with silica-gel column chromatography
  12. washeluting with 60:1 dichloromethane/methanol

Sources & evidence

ORD record
ord-61907bac6f4048b788179abb054b76f1
Source dataset
uspto-grants-2014_06
Patent number
US08754077B2

Reaction notes

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