Sodium Chloride → 3-(2-fluorophenyl)-7-(1-hydroxycyclobutyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine

HRID 2306595Notes

Reaction equation

HRID 2306595 reaction equation
[CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[N:5][CH:4]=[N:3]1.[H-].[Na+].Cl[C:12]1[C:13]([C:28]2([OH:32])[CH2:31][CH2:30][CH2:29]2)=[CH:14][C:15]2[N:16]([C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])=[N:19][N:20]=2)[N:17]=1.[NH4+].[Cl-].[Na+].[Cl-]>CN(C=O)C.ClCCl>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[N:16]2[N:17]=[C:12]([O:8][CH2:7][C:6]3[N:2]([CH3:1])[N:3]=[CH:4][N:5]=3)[C:13]([C:28]3([OH:32])[CH2:31][CH2:30][CH2:29]3)=[CH:14][C:15]2=[N:20][N:19]=1

Participants

8

Reactant 5

HCID 5234Sodium ChlorideHCID 24758Sodium hydrideHCID 25517Ammonium ChlorideHCID 11073377(1-methyl-1H-1,2,4-triazol-5-yl)methanolHCID 226099106-Chloro-3-(2-fluorophenyl)-7-(1-hydroxycyclobutyl)-1,2,4-triazolo[4,3-b]pyridazine

Product 1

HCID 226099353-(2-fluorophenyl)-7-(1-hydroxycyclobutyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazineYield 87.5%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 6344DichloromethaneSolvent

Procedure

To a stirred solution of (2-methyl-2H-1,2,4-triazol-3-yl)methanol (0.2206 g, 1.95 mmol) in anhydrous DMF (6 ml) under nitrogen was added sodium hydride (60% dispersion in oil, 77.7 mg, 1.94 mmol) and the mixture was stirred at room temperature for 20 min. The mixture was then cooled in an ice-water bath and a solution of 6-chloro-3-(2-fluorophenyl)-7-(1-hydroxycyclobutyl)-1,2,4-triazolo[4,3-b]pyridazine (0.2573 g, 0.807 mmol) in anhydrous DMF (5 ml) was added dropwise over 5 min. The mixture was stirred for 20 min under nitrogen, then poured into saturated aqueous NH4Cl (50 ml), saturated aqueous NaCl (25 ml), and dichloromethane (75 ml). The aqueous-layer was further extracted with dichloromethane (2×50 ml), and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 3-5% MeOH/CH2Cl2) to afford 0.2793 g of 3-(2-fluorophenyl)-7-(1-hydroxycyclobutyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine (containing approximately 20% of (2-methyl-2H-1,2,4-triazol-3-yl)methanol starting material) as a colourless solid; 1H NMR (360 MHz, CDCl3) δ 1.74 (1H, m), 2.17 (1H, m), 2.43 (2H, m), 2.60 (2H, m), 3.82 (3H, s), 5.58 (2H, s), 7.27 (1H, t, J=9.6 Hz), 7.36 (1H, t, J=7.5 Hz), 7.58 (1H, m), 7.82 (1H, m), 7.85 (1H, s), 8.01 (1H, s); MS (ES+) m/e 396 [MH]+, 114.

Workup

  1. temperatureThe mixture was then cooled in an ice-water bath
  2. stirringThe mixture was stirred for 20 min under nitrogen
  3. extractionThe aqueous-layer was further extracted with dichloromethane (2×50 ml)
  4. dry with materialthe combined organic extracts were dried (Na2SO4)
  5. customevaporated in vacuo
  6. customThe residue was purified by flash chromatography (silica gel, 3-5% MeOH/CH2Cl2)

Sources & evidence

ORD record
ord-899e56a51bff4590929d7126c4844d47
Source dataset
uspto-grants-2004_12
Patent number
US06828322B2

Reaction notes

Loading…