Potassium Phosphate, Tribasic → 2-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(1-methyl-5-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)nicotinaldehyde

HRID 1185118Notes

Reaction equation

HRID 1185118 reaction equation
[CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:27]=[C:21]3[CH2:22][N:23]([CH3:26])[CH2:24][CH2:25][N:20]3[N:19]=2)[C:3]1=[O:28].[C:29]([C:33]1[CH:34]=[C:35]2[C:40](=[C:41]([F:43])[CH:42]=1)[C:39](=[O:44])[N:38]([C:45]1[N:52]=[CH:51][CH:50]=[C:49](Cl)[C:46]=1[CH:47]=[O:48])[N:37]=[CH:36]2)([CH3:32])([CH3:31])[CH3:30].[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:29]([C:33]1[CH:34]=[C:35]2[C:40](=[C:41]([F:43])[CH:42]=1)[C:39](=[O:44])[N:38]([C:45]1[N:52]=[CH:51][CH:50]=[C:49]([C:6]3[CH:5]=[C:4]([NH:17][C:18]4[CH:27]=[C:21]5[CH2:22][N:23]([CH3:26])[CH2:24][CH2:25][N:20]5[N:19]=4)[C:3](=[O:28])[N:2]([CH3:1])[CH:7]=3)[C:46]=1[CH:47]=[O:48])[N:37]=[CH:36]2)([CH3:32])([CH3:30])[CH3:31]

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 517045Sodium AcetateHCID 866839152-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-chloronicotinaldehydeHCID 866839771-Methyl-3-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one

Product 1

HCID 866839762-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(1-methyl-5-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)nicotinaldehydeYield 65.2%

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 25-mL round-bottomed flask equipped with a reflux condenser was charged with 128d (193 mg, 0.50 mmol), 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-chloronicotinaldehyde 103b (180 mg, 0.50 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (17 mg, 0.025 mmol), K3PO4 (212 mg, 1.0 mmol), sodium acetate (82 mg, 1.0 mmol), acetonitrile (6 mL), and water (0.5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 1 h. Analysis of the reaction mixture by LCMS showed completed conversion to the desired product. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with dichloromethane (20 mL) and water (10 mL). The aqueous layer was separated and extracted with dichloromethane (3×10 mL). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80:1 to 30:1) to afford 128e (190 mg, 65%) as a yellow solid. MS-ESI: [M+H]+ 583.3

Workup

  1. customA 25-mL round-bottomed flask equipped with a reflux condenser
  2. customAfter three cycles of vacuum/argon flush
  3. temperatureThe reaction mixture was cooled to room temperature
  4. concentrationconcentrated under reduced pressure
  5. additionThe residue was diluted with dichloromethane (20 mL) and water (10 mL)
  6. customThe aqueous layer was separated
  7. extractionextracted with dichloromethane (3×10 mL)
  8. dry with materialThe combined organic layer was dried over Na2SO4
  9. filtrationfiltered
  10. concentrationThe filtrate was concentrated under reduced pressure
  11. customThe dark residue was purified by silica-gel column chromatography
  12. washeluting with dichloromethane/methanol (80:1 to 30:1)

Sources & evidence

ORD record
ord-f8e736fab7f64558bdaa7aa7ca87f3d6
Source dataset
uspto-grants-2014_03
Patent number
US08669251B2

Reaction notes

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