Citric Acid → 6-((6-Bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)imidazo[1,2-b]pyridazine-2-carbonyl azide

HRID 1925142Notes

Reaction equation

HRID 1925142 reaction equation
[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:25])([F:24])[C:12]3[CH:13]=[CH:14][C:15]4[N:16]([CH:18]=[C:19]([C:21](O)=[O:22])[N:20]=4)[N:17]=3)=[N:9][N:10]=2)[CH:7]=1.C(N(C(C)C)C(C)C)C.[N-:35]=[N+:36]=[N-:37].[Na+].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:25])([F:24])[C:12]3[CH:13]=[CH:14][C:15]4[N:16]([CH:18]=[C:19]([C:21]([N:35]=[N+:36]=[N-:37])=[O:22])[N:20]=4)[N:17]=3)=[N:9][N:10]=2)[CH:7]=1

Participants

8

Reactant 5

HCID 311Citric AcidHCID 33557Sodium AzideHCID 81531DiisopropylethylamineHCID 2724699PyBOPHCID 592331396-((6-Bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)imidazo[1,2-b]pyridazine-2-carboxylic acid

Product 1

HCID 866398206-((6-Bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)imidazo[1,2-b]pyridazine-2-carbonyl azideYield 92%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a stirred solution of 6-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)imidazo[1,2-b]pyridazine-2-carboxylic acid (3.5 g, 8.55 mmol), N-ethyl-N-isopropylpropan-2-amine (6.63 g, 51.3 mmol) and sodium azide (5.56 g, 86 mmol) in anhydrous DMF (60 mL), PyBOP (5.34 g, 10.27 mmol) was added in portions at ambient temperature over 5 min. The reaction was stirred for an additional 30 min and diluted with EtOAc (200 mL). The reaction was then poured into a 10% aqueous citric acid (200 mL), and the organic phase was separated and washed with citric acid solution (2×100 mL), saturated NaHCO3 (3×100 mL), and saturated NaCl solution. The aqueous phases were back extracted with EtOAc (200 mL) and the organic phases were combined, dried with MgSO4, filtered, and concentrated to dryness via rotary evaporation. The resulting residue was triturated in 1:1 Et2O/hexane, and the solid was collected by filtration and dried in vacuum over P2O5 to provide the title compound, 6-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)imidazo[1,2-b]pyridazine-2-carbonyl azide 45K (3.2 g, 7.37 mmol, 92%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.77 (dd, J=9.85, 1.77 Hz, 1 H) 7.88 (d, J=9.60 Hz, 1 H) 8.00-8.05 (m, 1 H) 8.56 (d, J=9.60 Hz, 1 H) 8.98 (s, 1 H) 9.14 (s, 1 H). ESI-MS:m/z 434.0 (M+H)+. ESI-MS:m/z 406.0 (M+H)+.

Workup

  1. customthe organic phase was separated
  2. washwashed with citric acid solution (2×100 mL), saturated NaHCO3 (3×100 mL), and saturated NaCl solution
  3. extractionThe aqueous phases were back extracted with EtOAc (200 mL)
  4. dry with materialdried with MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated to dryness via rotary evaporation
  7. customThe resulting residue was triturated in 1:1 Et2O/hexane
  8. filtrationthe solid was collected by filtration
  9. dry with materialdried in vacuum over P2O5

Sources & evidence

ORD record
ord-f6b946f311f64229984f78338e1719c5
Source dataset
uspto-grants-2012_05
Patent number
US08178534B2

Reaction notes

Loading…