Potassium Phosphate, Tribasic → (4-(5-Bromo-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyridin-3-yl)methyl acetate

HRID 407759Notes

Reaction equation

HRID 407759 reaction equation
[Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6](I)[CH:7]=1.[C:11]([O:14][CH2:15][C:16]1[C:17]([N:31]2[N:40]=[CH:39][C:38]3[C:33](=[C:34]([F:45])[CH:35]=[C:36]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:37]=3)[C:32]2=[O:46])=[N:18][CH:19]=[CH:20][C:21]=1B1OC(C)(C)C(C)(C)O1)(=[O:13])[CH3:12].C([O-])(=O)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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(#N)C>[C:11]([O:14][CH2:15][C:16]1[C:17]([N:31]2[N:40]=[CH:39][C:38]3[C:33](=[C:34]([F:45])[CH:35]=[C:36]([C:41]([CH3:43])([CH3:42])[CH3:44])[CH:37]=3)[C:32]2=[O:46])=[N:18][CH:19]=[CH:20][C:21]=1[C:6]1[CH:7]=[C:2]([Br:1])[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1)(=[O:13])[CH3:12]

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 517045Sodium AcetateHCID 86683972(2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methyl acetateHCID 866840253-Bromo-5-iodo-1-methyl-1,2-dihydropyridin-2-one

Product 1

HCID 86684026(4-(5-Bromo-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyridin-3-yl)methyl acetateYield 32.9%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
30 °C

Procedure

A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 142b, (1.37 g, 4.38 mmol, 1.0 eq.), 3-(acetoxymethyl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyridine-4-ylboronic acid 116c (2.07 mg, 5.0 mmol), Pd(dppf)Cl2 (179 mg, 0.219 mmol, 0.050 eq.), sodium acetate (718 mg, 8.76 mmol, 2.0 eq.), K3PO4 (1.86 g, 8.76 mmol, 2.0 eq.), acetonitrile (20 mL), and water (1 mL). After three cycles of vacuum/argon flush, the mixture was heated at 30° 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 100:1 dichloromethane/ethanol to afford 142c (800 mg, 32%) as a yellow solid. MS-ESI: [M+H]+ 555.2. 1H NMR (500 MHz, DMSO-d6) δ 8.66 (d, J=5.0 Hz, 1H), 8.56 (d, J=2.5 Hz, 1H), 8.14 (d, J=2.5 Hz, 1H), 8.08 (d, J=2.0 Hz, 1H), 7.91 (d, J=1.5 Hz, 1H), 7.82-7.79 (m, 1H), 7.62 (d, J=6.5 Hz, 1H), 5.02 (s, 2H), 3.59 (s, 3H), 1.78 (s, 3H), 1.40 (s, 9H).

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 100:1 dichloromethane/ethanol

Sources & evidence

ORD record
ord-3494ae0c9b3c40eca053f1b963e1b225
Source dataset
uspto-grants-2014_06
Patent number
US08754077B2

Reaction notes

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