Cesium carbonate → (+/-)-5-{[4-(6-Methylpyridin-3-yl)phenyl]methyl}-2-(tetrahydro-2H-pyran-3-yl)-2,5-dihydro-3H-pyrazolo[4,3-c]pyrido[3,2-e]pyridazin-3-one

HRID 2067119Notes

Reaction equation

HRID 2067119 reaction equation
I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3=[N:19][N:20]([CH:23]4[CH2:28][CH2:27][CH2:26][O:25][CH2:24]4)[C:21](=[O:22])[C:11]3=[N:10]2)=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][N:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)(O)[O-].[Na+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Cu]Cl>[CH3:29][C:30]1[N:31]=[CH:32][C:33]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][N:9]3[C:14]4[N:15]=[CH:16][CH:17]=[CH:18][C:13]=4[C:12]4=[N:19][N:20]([CH:23]5[CH2:28][CH2:27][CH2:26][O:25][CH2:24]5)[C:21](=[O:22])[C:11]4=[N:10]3)=[CH:4][CH:3]=2)=[CH:34][CH:35]=1

Participants

9

Reactant 4

HCID 10796Cesium carbonateHCID 516892Sodium BicarbonateHCID 27630812-Methylpyridine-5-boronic acidHCID 66744325(+/-)-5-[(4-iodophenyl)methyl]-2-(tetrahydro-2H-pyran-3-yl)-2,5-dihydro-3H-pyrazolo[4,3-c]pyrido[3,2-e]pyridazin-3-one

Product 1

HCID 49763461(+/-)-5-{[4-(6-Methylpyridin-3-yl)phenyl]methyl}-2-(tetrahydro-2H-pyran-3-yl)-2,5-dihydro-3H-pyrazolo[4,3-c]pyrido[3,2-e]pyridazin-3-one

Reagents, catalysts & solvents 4

HCID 62652Cuprous chlorideCatalystHCID 167845palladium(II) acetateCatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 6228DimethylformamideSolvent

Procedure

(±)-5-[(4-Iodophenyl)methyl]-2-(tetrahydro-2H-pyran-3-yl)-2,5-dihydro-3H-pyrazolo[4,3-c]pyrido[3,2-e]pyridazin-3-one [(Example 10, Step 3), 50 mg, 0.10 mmol], 2-methyl-5-pyridinylboronic acid (35 mg, 0.26 mmol, 2.5 equiv), palladium(II) acetate (4.6 mg, 0.21 mmol, 0.2 equiv), 1,1′-bis(diphenylphosphino)ferrocene (11 mg, 0.21 mmol, 0.2 equiv), copper(I) chloride (10 mg, 0.10 mmol, 1 equiv) and cesium carbonate (84 mg, 0.26 mmol, 2.5 equiv) were combined in degassed N,N′-dimethylformamide (3 mL) and placed in a preheated oil bath at 100° C. for 1 hour. The mixture was cooled to ambient temperature, poured into sodium bicarbonate (20 mL, aqueous saturated) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel gradient chromatography (100:0 to 90:10; dichloromethane:methanol), providing the titled compound as a deep red solid: 1H-NMR (hydrochloride salt, 400 MHz, CDCl3) δ 8.78 (2H, br s), 8.59 (1H, d, J=6.8 Hz), 8.39 (1H, br s), 7.72 (3H, br s), 7.55 (3H, br s), 6.02 (2H, s), 4.67 (1H, br s), 4.03-3.95 (2H, m), 3.79-3.70 (1H, m), 3.51-3.45 (1H, m), 3.02 (3H, br s), 2.36-2.06 (2H, m), 1.90-1.80 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 453.2039 [(M+H)+; calculated for C26H25N6O2: 453.2034].

Workup

  1. extractionextracted with ethyl acetate (3×20 mL)
  2. dry with materialThe combined organic extracts were dried with sodium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated in vacuo
  5. customThe residue was purified via silica gel gradient chromatography (100:0 to 90:10; dichloromethane:methanol)

Sources & evidence

ORD record
ord-9812e488bcea45269e8869b8bbbacff9
Source dataset
uspto-grants-2012_10
Patent number
US08293744B2

Reaction notes

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