Tetrahydrofuran → 7-Methoxy-N-((6-(3,4,5-trifluorophenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine

HRID 40230

Reaction equation

HRID 40230 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([CH2:19][NH2:20])=[CH:17][N:18]=3)[N:15]=2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].FC1C=C([C:30]2[CH:31]=[CH:32][C:33]3[N:34]([C:36](CO)=CN=3)[N:35]=2)C=C(F)C=1F.C(N(CC)CC)C.N([Na])=[N+]=[N-].CP(C)C.[CH2:56]1[CH2:60][O:59][CH2:58][CH2:57]1>C(Cl)Cl.O.CCOC(C)=O>[CH3:58][O:59][C:60]1[CH:56]=[C:57]2[C:33]([C:32]([NH:20][CH2:19][C:16]3[N:14]4[N:15]=[C:10]([C:4]5[CH:5]=[C:6]([F:9])[C:7]([F:8])=[C:2]([F:1])[CH:3]=5)[CH:11]=[CH:12][C:13]4=[N:18][CH:17]=3)=[CH:31][CH:30]=[N:35]2)=[N:34][CH:36]=1

Participants

10

Reactant 6

HCID 8028TetrahydrofuranHCID 8471TriethylamineHCID 68983TrimethylphosphineHCID 67502440(6-(3,4,5-Trifluorophenyl)imidazo[1,2-b]pyridazin-3-yl)methanolHCID 68925952(6-(3,4,5-Trifluorophenyl)imidazo[1,2-b]pyridazin-3-yl)methanamineHCID 178514644HCID 178514644, compound2×

Product 1

HCID 576909397-Methoxy-N-((6-(3,4,5-trifluorophenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine

Reagents, catalysts & solvents 3

HCID 962WaterSolvent2×HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent2×

Procedure

(6-(3,4,5-Trifluorophenyl)imidazo[1,2-b]pyridazin-3-yl)methanamine. To a suspension of (6-(3,4,5-trifluorophenyl)imidazo[1,2-b]pyridazin-3-yl)methanol (0.442 g, 1.6 mmol) in CH2Cl2 (5 mL) was added Mesyl-Cl (0.37 ml, 4.7 mmol) and triethylamine (0.66 ml, 4.7 mmol)-slight exotherm, place flask in water bath- and the mixture stirred at rt 1 h. The mixture was concentrated in vacuo (without heating the flask) and the residue dissolved in DMF (2 mL) and azidosodium (0.23 g, 3.5 mmol) was added in one portion. After 45 minutes, additional azidosodium (0.40 g, 6.0 mmol) was added and the mixture stirred 1 h longer. The mixture was diluted with EtOAc, washed with water, brine, (back extract aq layer) and dry organic layer over Na2SO4, filter and evaporate. The azide intermediate was dissolved in THF (4 mL) and trimethylphosphine 1M in THF (2.4 ml, 2.4 mmol) was added. The reaction mixture was stir at rt until the bubbling stops, plus an additional 2 minutes, then water (1 mL) was added. The mixture was diluted with EtOAc, washed with NaHCO3 solution, sat. NaHCO3, (back extract aq layer), then dry organic layer over Na2SO4, filter and evaporate. The residue was purified via flash chromatography using al % NH4OH in MeOH in CH2Cl2 gradient to afford the title compound as a tan solid.

Workup

  1. concentrationThe mixture was concentrated in vacuo (
  2. temperaturewithout heating the flask) and the residue
  3. dissolutiondissolved in DMF (2 mL)
  4. waitAfter 45 minutes
  5. stirringthe mixture stirred 1 h longer
  6. washwashed with water, brine
  7. filtration(back extract aq layer) and dry organic layer over Na2SO4, filter
  8. customevaporate
  9. dissolutionThe azide intermediate was dissolved in THF (4 mL)
  10. stirringThe reaction mixture was stir at rt until the bubbling
  11. washwashed with NaHCO3 solution, sat. NaHCO3
  12. filtration(back extract aq layer), then dry organic layer over Na2SO4, filter
  13. customevaporate
  14. customThe residue was purified via flash chromatography

Sources & evidence

ORD record
ord-c96f8d0c091e4e40bc3ad87e525d0f84
Source dataset
uspto-grants-2013_09
Patent number
US08524900B2

Linked notes

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