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

HRID 449708

Reaction equation

HRID 449708 reaction equation
Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:24]([O:27][CH2:28][C:29]1[C:34]([N:35]2[N:44]=[CH:43][C:42]3[C:37](=[C:38]([F:49])[CH:39]=[C:40]([C:45]([CH3:48])([CH3:47])[CH3:46])[CH:41]=3)[C:36]2=[O:50])=[CH:33][CH:32]=[CH:31][C:30]=1[B-](F)(F)F)(=[O:26])[CH3:25].[K+].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+]>C(O)CCC.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:24]([O:27][CH2:28][C:29]1[C:30]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([CH:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)=[CH:13][N:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=2)=[CH:31][CH:32]=[CH:33][C:34]=1[N:35]1[N:44]=[CH:43][C:42]2[C:37](=[C:38]([F:49])[CH:39]=[C:40]([C:45]([CH3:47])([CH3:46])[CH3:48])[CH:41]=2)[C:36]1=[O:50])(=[O:26])[CH3:25]

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 667423806-Chloro-2-methyl-4-(5-(1-methylpiperidin-4-yl)pyridin-2-ylamino)pyridazin-3(2H)-oneHCID 87134390potassium (2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate

Product 1

HCID 667426042-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(1-methyl-5-(5-(1-methylpiperidin-4-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)benzyl acetateYield 75.6%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 22253497Water butanolSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of 6-chloro-2-methyl-4-(5-(1-methylpiperidin-4-yl)pyridin-2-ylamino)pyridazin-3(2H)-one (1.06 g, 3.18 mmol), potassium (2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate (1.51 g, 3.18 mmol), xPhos (227 mg, 476 μmol) and potassium phosphate (1.48 g, 6.99 mmol) in 60 ml of butanol/water (5:1) was degassed with nitrogen for 10 minutes and bis(dibenzylideneacetone)palladium (0) (137 mg, 238 mmol) was added. The reaction mixture was heated to 110° C. for 3 hr. The crude reaction mixture was extracted with DCM, washed with water, dried over Na2SO4, filtered and concentrated to form a solid during concentration. This solid was triturated with ether to afford 1.67 g of crude product. Combined with 300 mg of crude material from a previous batch and purified by silica chromatography to afford 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(1-methyl-5-(5-(1-methylpiperidin-4-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)benzyl acetate (1.6 g) as a white solid.

Workup

  1. customwas degassed with nitrogen for 10 minutes
  2. customThe crude reaction mixture
  3. extractionwas extracted with DCM
  4. washwashed with water
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customto form a solid
  9. concentrationduring concentration
  10. customThis solid was triturated with ether
  11. customto afford 1.67 g of crude product
  12. custompurified by silica chromatography

Sources & evidence

ORD record
ord-c26d48dfcfca48a1aebaf48f2d03bf83
Source dataset
uspto-grants-2013_07
Patent number
US08481540B2

Linked notes

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