Cesium carbonate → 2-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(5-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)nicotinaldehyde

HRID 1185128Notes

Reaction equation

HRID 1185128 reaction equation
[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21](Cl)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[N:26]1[N:34]2[C:29]([CH2:30][O:31][CH2:32][CH2:33]2)=[CH:28][C:27]=1[NH:35][C:36]1[C:37](=[O:52])[N:38]([CH3:51])[CH:39]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:41]=1.P(C1CCCCC1)(C1CCCCC1)C1CCCCC1.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].O1CCOCC1.O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:40]3[CH:41]=[C:36]([NH:35][C:27]4[CH:28]=[C:29]5[CH2:30][O:31][CH2:32][CH2:33][N:34]5[N:26]=4)[C:37](=[O:52])[N:38]([CH3:51])[CH:39]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 75806TricyclohexylphosphineHCID 580440283-(6,7-Dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylamino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-oneHCID 866839152-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-chloronicotinaldehyde

Product 1

HCID 866839832-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(5-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)nicotinaldehydeYield 80%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
100 °C

Procedure

A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-chloronicotinaldehyde 103b (216 mg, 1 eq., 0.60 mmol), 131d (446 mg, 2 eq., 1.2 mmol), Pd2(dba)3 (55 mg, 0.1 eq., 0.060 mmol), Cy3P (67 mg, 0.4 eq., 0.24 mmol), Cs2CO3 (395 mg, 2 eq., 1.2 mmol), water (0.5 mL), and dioxane (10 mL). After three cycles of vacuum/N2 flush, the reaction mixture was stirred at 100° C. for 2 hrs. It was then cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 4:1 petroleum ether/ethyl acetate to afford 131e (272 mg, 80%) as a brown solid. MS-ESI: [M+H]+ 569.8

Workup

  1. customA 50-mL round-bottomed flask equipped with a reflux condenser
  2. customAfter three cycles of vacuum/N2 flush
  3. temperatureIt was then cooled to room temperature
  4. filtrationfiltered
  5. customThe filtrate was evaporated under reduced pressure
  6. customthe resulting residue was purified by silica-gel column chromatography
  7. washeluting with 4:1 petroleum ether/ethyl acetate

Sources & evidence

ORD record
ord-a835cb9138a1424eb5444effbe374938
Source dataset
uspto-grants-2014_03
Patent number
US08669251B2

Reaction notes

Loading…