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 1369436Notes

Reaction equation

HRID 1369436 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 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) δ1.74 (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-4d522f2f599649ecaf70083a52813870
Source dataset
uspto-grants-2003_06
Patent number
US06579875B1

Reaction notes

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