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

HRID 407797Notes

Reaction equation

HRID 407797 reaction equation
[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21](Cl)[C:18]=1[CH:19]=[O:20])C=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[CH:26]([N:29]1[C:34](=[O:35])[CH2:33][N:32]2[N:36]=[C:37]([NH:39][C:40]3[C:41](=[O:56])[N:42]([CH3:55])[CH:43]=[C:44](B4OC(C)(C)C(C)(C)O4)[CH:45]=3)[CH:38]=[C:31]2[CH2:30]1)([CH3:28])[CH3:27].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+].C(#[N:72])C>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:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:44]3[CH:45]=[C:40]([NH:39][C:37]4[CH:38]=[C:31]5[CH2:30][N:29]([CH:26]([CH3:28])[CH3:27])[C:34](=[O:35])[CH2:33][N:32]5[N:36]=4)[C:41](=[O:56])[N:42]([CH3:55])[CH:43]=3)[C:18]=1[CH:19]=[O:20])[N:72]=[CH:8]2)([CH3:3])([CH3:4])[CH3:2]

Participants

8

Reactant 5

HCID 6342AcetonitrileHCID 62657Potassium Phosphate, TribasicHCID 517045Sodium AcetateHCID 866840642-(6-tert-butyl-8-fluoro-1-oxoisoquinolin-2(1H)-yl)-4-chloronicotinaldehydeHCID 895521485-Isopropyl-2-(1-methyl-2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-3-ylamino)-4,5-dihydropyrazolo[1,5-a]pyrazin-6(7H)-one

Product 1

HCID 866840592-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(5-(5-isopropyl-6-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)nicotinaldehydeYield 48%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolvent2×

Conditions

Temperature
80 °C

Procedure

A 25-mL round-bottomed flask equipped with a reflux condenser was charged with 2-(6-tert-butyl-8-fluoro-1-oxoisoquinolin-2(1H)-yl)-4-chloronicotinaldehyde 103b (108 mg, 0.30 mmol), 151g (256 mg, 0.60 mmol), K3PO4 (127 mg, 0.60 mmol), sodium acetate.water (82 mg, 0.60 mmol), Pd(dppf)Cl2 (12 mg, 0.015 mmol), water (0.5 mL), and acetonitrile (8 mL). The reaction mixture was subjected to three cycles of vacuum/nitrogen flush and heated at 80° C. under N2 protection for 2 h. It was then cooled to room temperature and concentrated under reduced pressure. The residue was diluted with dichloromethane (20 mL) and water (10 mL). The organic layer was separated and the water layer was extracted with dichloromethane (2×10 mL). The combined organic extract was dried over Na2SO4, filtered, and 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 151h (90 mg, 48%) as yellow solid. MS-ESI: [M+H]+ 625.2.

Workup

  1. customA 25-mL round-bottomed flask equipped with a reflux condenser
  2. customflush
  3. temperatureIt was then cooled to room temperature
  4. concentrationconcentrated under reduced pressure
  5. additionThe residue was diluted with dichloromethane (20 mL) and water (10 mL)
  6. customThe organic layer was separated
  7. extractionthe water layer was extracted with dichloromethane (2×10 mL)
  8. extractionThe combined organic extract
  9. dry with materialwas dried over Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. customThe dark residue was purified by silica-gel column chromatography
  13. washeluting with dichloromethane/methanol (80:1 to 30:1)

Sources & evidence

ORD record
ord-c47d384b9c9b429596970f3d9723a83c
Source dataset
uspto-grants-2014_06
Patent number
US08754077B2

Reaction notes

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