Potassium Carbonate → (+/-)-5-[(6'-methyl-2,3'-bipyridin-5-yl)methyl]-2-(tetrahydro-2H-pyran-3-yl)-2,5-dihydro-3H-pyrazolo[4,3-c]pyrido[3,2-e]pyridazin-3-one

HRID 2067114Notes

Reaction equation

HRID 2067114 reaction equation
C[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH2:14][N:15]1[C:20]2[N:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18](=S)[C:17]([C:26](OCC)=[O:27])=[N:16]1.Cl.[O:32]1[CH2:37][CH2:36][CH2:35][CH:34]([NH:38][NH2:39])[CH2:33]1.[C:40](=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>C(O)C.O1CCOCC1.CN(C=O)C>[CH3:40][C:11]1[N:10]=[CH:9][C:8]([C:6]2[CH:5]=[CH:4][C:3]([CH2:14][N:15]3[C:20]4[N:21]=[CH:22][CH:23]=[CH:24][C:19]=4[C:18]4=[N:39][N:38]([CH:34]5[CH2:35][CH2:36][CH2:37][O:32][CH2:33]5)[C:26](=[O:27])[C:17]4=[N:16]3)=[CH:2][N:7]=2)=[CH:13][CH:12]=1

Participants

8

Reactant 4

HCID 11430Potassium CarbonateHCID 516892Sodium BicarbonateHCID 66744316(Tetrahydro-2H-pyran-3-yl)hydrazine hydrochlorideHCID 86662100Ethyl 1-[(6-methyl-2,3'-bipyridin-5-yl)methyl]-4-thioxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxylate

Product 1

HCID 49763348(+/-)-5-[(6'-methyl-2,3'-bipyridin-5-yl)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 3

HCID 702EthanolSolventHCID 6228DimethylformamideSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

Ethyl 1-[(6-methyl-2,3′-bipyridin-5-yl)methyl]-4-thioxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxylate [(Example 6, Step 2), 125 mg, 0.299 mmol], (±)-tetrahydro-2H-pyran-3-ylhydrazine hydrochloride (91.0 mg, 0.599 mmol, 2 equiv) and potassium carbonate (414 mg, 2.99 mmol, 10 equiv) were combined in ethanol (10 mL), N,N′-dimethylformamide (3 mL) and dioxane (5 mL) at ambient temperature and after 5 minutes, were warmed to 80° C. for 4 hours. The mixture was cooled to ambient temperature, poured into sodium bicarbonate (100 mL, aqueous saturated) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate containing 10% methanol), providing the titled compound as a deep red solid: 1H-NMR (400 MHz, CDCl3) δ 9.02 (1H, d, J=2.1 Hz), 8.93 (1H, d, J=2.3 Hz), 8.75 (1H, dd, J=4.6, 1.8 Hz), 8.51 (1H, dd, J=8.1, 1.8 Hz), 8.16 (1H, dd, J=8.1, 2.4 Hz), 7.97 (1H, dd, J=8.2, 2.3 Hz), 7.66 (1H, dd, J=8.2, 0.6 Hz), 7.50 (1H, dd, J=7.9, 4.6 Hz), 7.24 (1H, d, J=8.1 Hz), 5.97 (1H, br s), 4.70-4.62 (1H, m), 4.01-3.94 (2H, m), 3.74 (1H, ap t, J=10.7 Hz), 3.49 (1H, br m), 3.45 (1H, dd, J=11.1, 3.4 Hz), 2.60 (3H, s), 2.21-2.05 (3H, m) ppm; high resolution mass spectrometry (ES+) m/z 454.1984 [(M+H)+; calculated for C25H24N7O2: 454.1986].

Workup

  1. temperatureThe mixture was cooled to ambient temperature
  2. extractionextracted with ethyl acetate (2×100 mL)
  3. dry with materialThe combined organic extracts were dried with sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate containing 10% methanol)

Sources & evidence

ORD record
ord-d3f27821ad52497582dfd0710332882d
Source dataset
uspto-grants-2012_10
Patent number
US08293744B2

Reaction notes

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