Acetonitrile → 2-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(5-(5-ethylisoxazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)nicotinaldehyde

HRID 1185230Notes

Reaction equation

HRID 1185230 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].[CH2:26]([C:28]1[O:32][N:31]=[C:30]([NH:33][C:34]2[C:35](=[O:50])[N:36]([CH3:49])[CH:37]=[C:38](B3OC(C)(C)C(C)(C)O3)[CH:39]=2)[CH:29]=1)[CH3:27].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+].C(#[N:66])C>O.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: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:38]3[CH:39]=[C:34]([NH:33][C:30]4[CH:29]=[C:28]([CH2:26][CH3:27])[O:32][N:31]=4)[C:35](=[O:50])[N:36]([CH3:49])[CH:37]=3)[C:18]=1[CH:19]=[O:20])[N:66]=[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 866840793-(5-Ethylisoxazol-3-ylamino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one

Product 1

HCID 866840782-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(5-(5-ethylisoxazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)nicotinaldehydeYield 88%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
100 °C

Procedure

A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-chloronicotinaldehyde 103b (160 mg, 0.44 mmol), 158b (228 mg, 0.66 mmol), Pd(dppf)Cl2 (18 mg, 0.022 mol), K3PO4 (187 mg, 0.88 mmol), sodium acetate (72.2 mg, 0.88 mmol), acetonitrile (15 mL), and water (5 drops). The system was subjected to three cycles of vacuum/nitrogen flush and heated at 100° C. under N2 protection for 1 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 40:1 dichloromethane/methanol to afford 158c (210 mg, 88%) as yellow oil. MS-ESI: [M+H]+ 543.3

Workup

  1. customA 50-mL round-bottomed flask equipped with a reflux condenser
  2. customflush
  3. temperatureIt was then cooled to room temperature
  4. filtrationfiltered
  5. concentrationThe filtrate was concentrated under reduced pressure
  6. customthe residue was purified by silica-gel column chromatography
  7. washeluting with 40:1 dichloromethane/methanol

Sources & evidence

ORD record
ord-1efacfef0330496480b3632429ec2730
Source dataset
uspto-grants-2014_03
Patent number
US08669251B2

Reaction notes

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