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

HRID 1431103Notes

Reaction equation

HRID 1431103 reaction equation
Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:26]([O:29][CH2:30][C:31]1[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=[CH:33][C:32]=1[N:46]1[N:55]=[CH:54][C:53]2[C:48](=[C:49]([F:60])[CH:50]=[C:51]([C:56]([CH3:59])([CH3:58])[CH3:57])[CH:52]=2)[C:47]1=[O:61])(=[O:28])[CH3:27].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:26]([O:29][CH2:30][C:31]1[C:36]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]4)=[CH:13][N:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=2)=[CH:35][CH:34]=[CH:33][C:32]=1[N:46]1[N:55]=[CH:54][C:53]2[C:48](=[C:49]([F:60])[CH:50]=[C:51]([C:56]([CH3:58])([CH3:57])[CH3:59])[CH:52]=2)[C:47]1=[O:61])(=[O:28])[CH3:27]

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 594737692-(6-(tert-Butyl)-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetateHCID 667422216-chloro-4-(5-(4-isopropylpiperazin-1-yl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one

Product 1

HCID 667431912-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(4-isopropylpiperazin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzyl acetateYield 78%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
125 °C

Procedure

6-Chloro-4-(5-(4-isopropylpiperazin-1-yl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one (123 mg, 340 μmol, Eq: 1.2), 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (140 mg, 283 μmol, Eq: 1.00), potassium phosphate tribasic (180 mg, 850 μmol, Eq: 3.00) and X-PHOS (13.5 mg, 28.3 μmol, Eq: 0.10) were dissolved in dioxane (10 ml) and water (1.0 mL). The reaction was degassed with Ar. Pd2(dba)3 (13.0 mg, 14.2 μmol, Eq: 0.05) was added and the reaction was heated to 125° C. for 30 min in the microwave. The solution was dried over MgSO4 and filtered. Concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 5% MeOH/DCM gradient) to give 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(4-isopropylpiperazin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzyl acetate (153 mg, 78%). LC/MS-ESI observed [M+H]+ 695.

Workup

  1. customThe reaction was degassed with Ar
  2. dry with materialThe solution was dried over MgSO4
  3. filtrationfiltered
  4. concentrationConcentrated in vacuo
  5. customThe crude material was purified by flash chromatography (silica gel, 12 g, 0% to 5% MeOH/DCM gradient)

Sources & evidence

ORD record
ord-1f43d5ec6cae498ba5df11def1f70776
Source dataset
uspto-grants-2015_01
Patent number
US08940741B2

Reaction notes

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