Cesium carbonate → Acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{1-methyl-5-[6-((1S,4S)-5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-pyridazin-3-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-benzyl ester

HRID 449661Notes

Reaction equation

HRID 449661 reaction equation
[CH3:1][N:2]1[CH2:7][C@@H:6]2[CH2:8][C@H:3]1[CH2:4][N:5]2[C:9]1[N:14]=[N:13][C:12]([NH2:15])=[CH:11][CH:10]=1.Br[C:17]1[C:22](=[O:23])[N:21]([CH3:24])[N:20]=[C:19]([C:25]2[CH:35]=[CH:34][CH:33]=[C:32]([N:36]3[N:45]=[CH:44][C:43]4[C:38](=[C:39]([F:50])[CH:40]=[C:41]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH:42]=4)[C:37]3=[O:51])[C:26]=2[CH2:27][O:28][C:29](=[O:31])[CH3:30])[CH:18]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>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:46]([C:41]1[CH:42]=[C:43]2[C:38](=[C:39]([F:50])[CH:40]=1)[C:37](=[O:51])[N:36]([C:32]1[CH:33]=[CH:34][CH:35]=[C:25]([C:19]3[CH:18]=[C:17]([NH:15][C:12]4[N:13]=[N:14][C:9]([N:5]5[CH2:4][C@@H:3]6[CH2:8][C@H:6]5[CH2:7][N:2]6[CH3:1])=[CH:10][CH:11]=4)[C:22](=[O:23])[N:21]([CH3:24])[N:20]=3)[C:26]=1[CH2:27][O:28][C:29](=[O:31])[CH3:30])[N:45]=[CH:44]2)([CH3:47])([CH3:48])[CH3:49]

Participants

6

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 667421922-(5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-6-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)benzyl acetateHCID 667430796-((1S,4S)-5-Methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-pyridazin-3-ylamine

Product 1

HCID 66743398Acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{1-methyl-5-[6-((1S,4S)-5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-pyridazin-3-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-benzyl ester

Reagents, catalysts & solvents 1

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Conditions

Temperature
100 °C

Procedure

6-((1S,4S)-5-Methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-pyridazin-3-ylamine (100 mg, 0.487 mmol, Eq: 1.00), acetic acid 2-(5-bromo-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-6-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-benzyl ester (284 mg, 0.512 mmol, Eq: 1.05), xantphos (42.3 mg, 0.073 mmol, Eq: 0.15), tris(dibenzylideneacetone)-dipalladium (0) (33.5 mg, 0.036 mmol, Eq: 0.075) and cesium carbonate (476 mg, 1.46 mmol, Eq: 3.00) were added to a microwave vial. The vial was capped and purged. Degassed dioxane (about 5 ml) was added through a syringe and the vial was purged again and back filled with nitrogen. The reaction was heated at 100° C. overnight in a sand bath. The reaction was filtered through celite and concentrated. The crude product was purified by chromatography using a gradient of 0% to 25% methanol in DCM. LCMS and NMR showed major impurities. Took on to next step without further purification.

Workup

  1. customThe vial was capped
  2. custompurged
  3. additionDegassed dioxane (about 5 ml) was added through a syringe
  4. customthe vial was purged again
  5. additionback filled with nitrogen
  6. filtrationThe reaction was filtered through celite
  7. concentrationconcentrated
  8. customThe crude product was purified by chromatography
  9. customTook on to next step without further purification

Sources & evidence

ORD record
ord-b328632016074ca0a970e618ec7a9266
Source dataset
uspto-grants-2013_07
Patent number
US08481540B2

Reaction notes

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