Potassium Phosphate, Tribasic → 2-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(5-(5-((2S,5R)-2,5-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)nicotinaldehyde

HRID 407631Notes

Reaction equation

HRID 407631 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][C@H:27]1[CH2:32][N:31]([CH:33]2[CH2:36][O:35][CH2:34]2)[C@H:30]([CH3:37])[CH2:29][N:28]1[C:38]1[CH:39]=[CH:40][C:41]([NH:44][C:45]2[C:46](=[O:60])[N:47]([CH3:59])[CH:48]=[C:49](B3OC(C)(C)C(C)O3)[CH:50]=2)=[N:42][CH:43]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC#N.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:49]3[CH:50]=[C:45]([NH:44][C:41]4[CH:40]=[CH:39][C:38]([N:28]5[CH2:29][C@@H:30]([CH3:37])[N:31]([CH:33]6[CH2:36][O:35][CH2:34]6)[CH2:32][C@@H:27]5[CH3:26])=[CH:43][N:42]=4)[C:46](=[O:60])[N:47]([CH3:59])[CH:48]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]

Participants

6

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 866839152-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-chloronicotinaldehydeHCID 866839293-(5-((2S,5R)-2,5-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methyl-5-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one

Product 1

HCID 866839282-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(5-(5-((2S,5R)-2,5-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)nicotinaldehydeYield 42%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
100 °C

Procedure

A 100-mL single-neck round-bottomed flask was charged with 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-chloronicotinaldehyde 103b (216 mg, 0.6 mmol), 3-(5-((2S,5R)-2,5-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methyl-5-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (360 mg, 0.72 mmol), Pd(dppf)Cl2 (30 mg, 0.03 mmol), K3PO4 (270 mg, 1.2 mmol), and NaOAc.3H2O (180 mg, 1.2 mmol) in CH3CN (80 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography eluting with 25:1 of CH2Cl2/MeOH to afford 110a (160 mg, 42%) as a yellow brown solid. MS: [M+H]+ 693.3.

Workup

  1. customThe system was evacuated
  2. additionrefilled with N2
  3. temperatureIt was then cooled to room temperature
  4. filtrationfiltered
  5. concentrationThe filtrate was concentrated under reduced pressure
  6. customthe resulting residue was purified by flash column chromatography
  7. washeluting with 25:1 of CH2Cl2/MeOH

Sources & evidence

ORD record
ord-6392635571db48de927933f8e5cb97d9
Source dataset
uspto-grants-2014_06
Patent number
US08754077B2

Reaction notes

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