p-Toluenesulfonic acid → ethyl 6-((6-bromo-1H-benzo[d][1,2,3]triazol-1-yl)methyl)imidazo[1,2-b]pyridazine-2-carboxylate

HRID 1925118Notes

Reaction equation

HRID 1925118 reaction equation
[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][N:7]([CH2:10][C:11]3[N:16]=[N:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[C:6]=2[CH:18]=1.Br[CH2:20][C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23].C([O-])(O)=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][N:7]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]4[N:15]([CH:20]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:17]=4)[N:16]=3)[C:6]=2[CH:18]=1

Participants

6

Reactant 4

HCID 6101p-Toluenesulfonic acidHCID 66144Ethyl bromopyruvate2×HCID 516892Sodium BicarbonateHCID 592330216-(6-Bromo-benzotriazol-1-ylmethyl)-pyridazin-3-ylamine

Product 1

HCID 66633612ethyl 6-((6-bromo-1H-benzo[d][1,2,3]triazol-1-yl)methyl)imidazo[1,2-b]pyridazine-2-carboxylateYield 73.7%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
60 °C

Procedure

A mixture of 6-((6-bromo-1H-benzo[d][1,2,3]triazol-1-yl)methyl)pyridazin-3-amine 10G (4.8 g, 15.73 mmol), ethyl 3-bromo-2-oxopropanoate (4.60 g, 23.60 mmol) and NaHCO3 (4.0 g) in dioxane was heated at 60° C. for 1 hr. Additional ethyl 3-bromo-2-oxopropanoate (1.5 g, 7.87 mmol, 0.5 eq) was added and stirred at 60° C. for an additional hour. The reaction mixture was filtered and rinsed with dioxane. 4-Methylbenzenesulfonic acid (2.71 g, 15.73 mmol) was added to the filtrate, and the reaction was heated at 75° C. for 2 hrs. The reaction was evaporated to dryness via rotary evaporation and the resulting residue was dissolved in EtOAc. The organic phase was washed with saturated NaHCO3 followed by 0.1 N NaOH (3×150 mL). The solution was dried with MgSO4, filtered, concentrated to dryness and purified by MPLC (10% MeOH/CH2Cl2) to provide the title compound, ethyl 6-((6-bromo-1H-benzo[d][1,2,3]triazol-1-yl)methyl)imidazo[1,2-b]pyridazine-2-carboxylate 13A (4.7 g, 11.6 mmol, 50%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (t, J=7.07 Hz, 3 H) 4.30 (q, J=7.07 Hz, 2 H) 6.26 (s, 2 H) 7.33 (d, J=9.60 Hz, 1 H) 7.59 (dd, J=8.72, 1.64 Hz, 1H) 8.08 (d, J=8.84 Hz, 1 H) 8.23 (d, J=9.60 Hz, 1 H) 8.31 (d, J=1.26 Hz, 1 H) 8.77 (s, 1 H). MS:m/z 401.2 (M+H)+.

Workup

  1. filtrationThe reaction mixture was filtered
  2. washrinsed with dioxane
  3. temperaturethe reaction was heated at 75° C. for 2 hrs
  4. customThe reaction was evaporated to dryness via rotary evaporation
  5. dissolutionthe resulting residue was dissolved in EtOAc
  6. washThe organic phase was washed with saturated NaHCO3
  7. dry with materialThe solution was dried with MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated to dryness
  10. custompurified by MPLC (10% MeOH/CH2Cl2)

Sources & evidence

ORD record
ord-172638dec4464c21bea82c7ac524ca2e
Source dataset
uspto-grants-2012_05
Patent number
US08178534B2

Reaction notes

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