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

HRID 449627

Reaction equation

HRID 449627 reaction equation
Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[N:13]([CH3:17])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:18]([O:21][CH2:22][C:23]1[C:28]([N:29]2[N:38]=[CH:37][C:36]3[C:31](=[C:32]([F:43])[CH:33]=[C:34]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:35]=3)[C:30]2=[O:44])=[CH:27][CH:26]=[CH:25][C:24]=1[B-](F)(F)F)(=[O:20])[CH3:19].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([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].O.C(O)CCC>[C:18]([O:21][CH2:22][C:23]1[C:24]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[CH:15]=[C:14]([CH3:16])[N:13]([CH3:17])[N:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=2)=[CH:25][CH:26]=[CH:27][C:28]=1[N:29]1[N:38]=[CH:37][C:36]2[C:31](=[C:32]([F:43])[CH:33]=[C:34]([C:39]([CH3:41])([CH3:40])[CH3:42])[CH:35]=2)[C:30]1=[O:44])(=[O:20])[CH3:19]

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 585400026-chloro-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-2-methylpyridazin-3(2H)-oneHCID 87134390potassium (2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate

Product 1

HCID 667431562-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(1,5-dimethyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzyl acetateYield 81%

Reagents, catalysts & solvents 3

HCID 6505921(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladiumCatalystHCID 2631-ButanolSolventHCID 962WaterSolvent

Conditions

Temperature
100 °C

Procedure

In a 50 mL test tube, 6-chloro-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-2-methylpyridazin-3(2H)-one (100 mg, 394 μmol, Eq: 1.00) and potassium (2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate (224 mg, 473 μmol, Eq: 1.2) were combined with BuOH (4.00 ml) to give a orange solution. Water (1.00 ml) was added. X-PHOS (18.8 mg, 39.4 μmol, Eq: 0.1) and potassium phosphate tribasic (167 mg, 788 μmol, Eq: 2) were added. Bis(dibenzylideneacetone)palladium (11.3 mg, 19.7 μmol, Eq: 0.05) was added. The reaction mixture was purged with argon. The solution warmed in a oil bath at 100° C. for 1.5 hours. The solution was allowed to cool to room temperature. The reaction mixture was poured into 75 mL H2O and extracted with DCM. The organic layer was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 25 g, 0% to 30% (60:10:1 DCM:MeOH:NH4OH)/DCM gradient) to give a solid. The solid was triturated with Et2O to give 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(1,5-dimethyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzyl acetate (186 mg, 81%). LC/MS-ESI observed [M+H]+ 586.

Workup

  1. customto give a orange solution
  2. customThe reaction mixture was purged with argon
  3. temperatureto cool to room temperature
  4. additionThe reaction mixture was poured into 75 mL H2O
  5. extractionextracted with DCM
  6. concentrationThe organic layer was concentrated in vacuo
  7. customThe crude material was purified by flash chromatography (silica gel, 25 g, 0% to 30% (60:10:1 DCM:MeOH:NH4OH)/DCM gradient)
  8. customto give a solid
  9. customThe solid was triturated with Et2O

Sources & evidence

ORD record
ord-a654cc3c6c654e2eb1efd25312f16a40
Source dataset
uspto-grants-2013_07
Patent number
US08481540B2

Linked notes

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