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

HRID 1185138Notes

Reaction equation

HRID 1185138 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])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][N:33]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:32]2[CH2:31]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>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(#N)C>[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:32]5[CH2:31][N:30]([CH2:29][CH2:28][O:27][CH3:26])[CH2:35][CH2:34][N:33]5[N:36]=4)[C:41](=[O:56])[N:42]([CH3:55])[CH:43]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 517045Sodium AcetateHCID 866839152-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-chloronicotinaldehydeHCID 866839943-(5-(2-Methoxyethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one

Product 1

HCID 866839932-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(5-(5-(2-methoxyethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)nicotinaldehydeYield 80%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
100 °C

Procedure

A 25-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 (100 mg, 0.28 mmol), 133d (144.4 mg, 0.42 mmol), Pd(dppf)Cl2 (11.3 mg, 0.0139 mmol), K3PO4 (117.8 mg, 0.556 mmol), sodium acetate (45.6 mg, 0.556 mmol), acetonitrile (10 mL), and water (3 drops). After three cycles of vacuum/N2 flush, the mixture was heated at 100° C. for 1 h under N2 protection. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. It was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 40:1 dichloromethane/methanol to afford 133e as a yellow solid (140 mg, 80%). MS-ESI: [M+H]+ 627.3

Workup

  1. customA 25-mL round-bottomed flask equipped with a reflux condenser
  2. customAfter three cycles of vacuum/N2 flush
  3. temperatureIt was 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-a8689f205f4b45c2aeb6e9720f73b506
Source dataset
uspto-grants-2014_03
Patent number
US08669251B2

Reaction notes

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