Potassium Phosphate, Tribasic → (R)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-fluoro-6-(1-methyl-5-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl)benzaldehyde

HRID 1185040Notes

Reaction equation

HRID 1185040 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:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([CH:30]4[CH2:33][O:32][CH2:31]4)[CH2:26][C@H:25]3[CH3:34])=[CH:20][N:19]=2)[C:3]1=[O:35].Br[C:37]1[CH:44]=[C:43]([F:45])[CH:42]=[C:41]([N:46]2[N:55]=[CH:54][C:53]3[C:48](=[C:49]([F:60])[CH:50]=[C:51]([C:56]([CH3:59])([CH3:58])[CH3:57])[CH:52]=3)[C:47]2=[O:61])[C:38]=1[CH:39]=[O:40].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC([O-])=O.[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.CC#N>[C:56]([C:51]1[CH:52]=[C:53]2[C:48](=[C:49]([F:60])[CH:50]=1)[C:47](=[O:61])[N:46]([C:41]1[CH:42]=[C:43]([F:45])[CH:44]=[C:37]([C:6]3[CH:5]=[C:4]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH2:29][CH2:28][N:27]([CH:30]6[CH2:31][O:32][CH2:33]6)[CH2:26][C@H:25]5[CH3:34])=[CH:20][N:19]=4)[C:3](=[O:35])[N:2]([CH3:1])[CH:7]=3)[C:38]=1[CH:39]=[O:40])[N:55]=[CH:54]2)([CH3:59])([CH3:57])[CH3:58]

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 517045Sodium AcetateHCID 866839112-Bromo-6-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-fluorobenzaldehydeHCID 866839191-methyl-3-[[5-[(2R)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]-2-pyridyl]amino]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one

Product 1

HCID 86683921(R)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-fluoro-6-(1-methyl-5-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl)benzaldehydeYield 31%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
80 °C

Procedure

A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with (R)-1-methyl-3-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (173 mg, 1.0 eq., 0.36 mmol), 2-bromo-6-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-fluorobenzaldehyde 101i (152 mg, 1.0 eq., 0.36 mmol), K3PO4 (152 mg, 2.0 eq., 0.72 mmol), PdCl2(dppf) (26 mg, 0.1 eq., 0.036 mmol), NaOAc (59 mg, 2.0 eq., 0.72 mmol), CH3CN (20 mL), and H2O (0.8 mL). After three cycles of vacuum/argon flush, the mixture was heated at 80° 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 silica-gel column chromatography eluting with 40:1 DCM/EtOH to afford 107a as yellow solid (77 mg, 31%). MS: [M+H]+ 696.3.

Workup

  1. customA 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser
  2. customAfter three cycles of vacuum/argon flush
  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 silica-gel column chromatography
  7. washeluting with 40:1 DCM/EtOH

Sources & evidence

ORD record
ord-ed70f1ac6bf34726b965d864b86f6350
Source dataset
uspto-grants-2014_03
Patent number
US08669251B2

Reaction notes

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