Potassium Phosphate, Tribasic → Acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{1-methyl-5-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-benzyl ester

HRID 449653Notes

Reaction equation

HRID 449653 reaction equation
Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:25]([O:28][CH2:29][C:30]1[C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=[CH:32][C:31]=1[N:45]1[N:54]=[CH:53][C:52]2[C:47](=[C:48]([F:59])[CH:49]=[C:50]([C:55]([CH3:58])([CH3:57])[CH3:56])[CH:51]=2)[C:46]1=[O:60])(=[O:27])[CH3:26].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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]>[C:55]([C:50]1[CH:51]=[C:52]2[C:47](=[C:48]([F:59])[CH:49]=1)[C:46](=[O:60])[N:45]([C:31]1[CH:32]=[CH:33][CH:34]=[C:35]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([CH2:17][N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)=[CH:13][N:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=3)[C:30]=1[CH2:29][O:28][C:25](=[O:27])[CH3:26])[N:54]=[CH:53]2)([CH3:56])([CH3:57])[CH3:58]

Participants

6

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 667423596-Chloro-2-methyl-4-(5-((4-methylpiperazin-1-yl)methyl)pyridin-2-ylamino)pyridazin-3(2H)-one

Product 1

HCID 66743194Acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{1-methyl-5-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-benzyl ester

Reagents, catalysts & solvents 1

HCID 6505921(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladiumCatalyst

Conditions

Temperature
115 °C

Procedure

6-Chloro-2-methyl-4-(5-((4-methylpiperazin-1-yl)methyl)pyridin-2-ylamino)pyridazin-3(2H)-one (3.1 g, 8.89 mmol, Eq: 1.00), 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 (7.69 g, 15.6 mmol, Eq: 1.75), X-PHOS (424 mg, 0.89 mmol, Eq: 0.10), bis(dibenzylideneacetone)palladium (255 mg, 0.44 mmol, Eq: 0.05) and tripotassium phosphate (4.72 g, 22.2 mmol, Eq: 2.50) were added to a large microwave vial. The vial was capped and purged. N-butanol (35.5 ml) and water (9 ml) were added and the vial was purged again and backfilled with nitrogen. The reaction was heated in a sand bath at 115° C. for 2.5 hours. Water and DCM were added to the reaction and the layers were separated. The organic layer was filtered through celite, concentrated, and purified by chromatography using a gradient of 0% to 25% methanol in DCM. Fractions with and without the protecting group were combined to give a combined yield of 4.5 g (approximately 74%).

Workup

  1. customThe vial was capped
  2. custompurged
  3. additionN-butanol (35.5 ml) and water (9 ml) were added
  4. customthe vial was purged again
  5. additionWater and DCM were added to the reaction
  6. customthe layers were separated
  7. filtrationThe organic layer was filtered through celite,
  8. concentrationconcentrated
  9. custompurified by chromatography
  10. customto give a combined yield of 4.5 g (approximately 74%)

Sources & evidence

ORD record
ord-7842ab5349f94111a6981f5aae64dca2
Source dataset
uspto-grants-2013_07
Patent number
US08481540B2

Reaction notes

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