Iodine → (6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-quinoline

HRID 69169Notes

Reaction equation

HRID 69169 reaction equation
O[PH2]=O.[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11]([CH:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=C[CH:20]=[CH:19]4)O)=[CH:12][N:13]=2)[N:10]=1.II>C(O)(=O)C>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11]([C:14]3[CH:16]=[CH:17][C:18]4[C:23](=[CH:24][CH:25]=[CH:20][CH:19]=4)[N:22]=3)=[CH:12][N:13]=2)[N:10]=1

Participants

5

Reactant 3

HCID 807IodineHCID 4124402Phosphinic AcidHCID 87524298(6-Chloroimidazo[1,2-b]pyridazin-3-yl)(quinolin-6-yl)methanol

Product 1

HCID 44206294(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-quinoline

Reagents, catalysts & solvents 1

HCID 176Acetic AcidSolvent

Conditions

Temperature
110 °C

Procedure

H3PO2 (28.8 mL of a 50% aqueous solution, 263 mmol) was added to a solution of (rac)-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-quinolin-6-yl-methanol (Stage 1.1, 10.89 g, 35.0 mmol) in acetic acid (272 mL) at 80° C. Iodine (13.34 g, 52.6 mmol) was then added and the RM was stirred at 110° C. for 90 min. The RM was cooled down to rt and acetic acid was removed. The residue was taken up in water and DCM. A 2 N NaOH solution was then added until pH=11. The organic layer was then separated and washed with water (2×). The aqueous layer was further extracted with DCM (3×). The combined organic layer was then dried, filtered and concentrated. The residue crystallized in EtOAc. The resulting solid was purified by flash chromatography (Flashmaster, with a 50 g silica gel column, TBME/MeOH: 97:3→84:16). The solid crystallized again in EtOAc/Et2O. It was filtered and dried under vacuum to afford the title compound as a white solid (tR 4.72 min (conditions 4), MH+=295.0, 1H-NMR in DMSO-d6: 8.86 (m, 1H); 8.30 (m, 1H); 8.23 (d, 1H); 7.98 (d, 1H); 7.82 (m, 1H); 7.72 (m, 2H); 7.50 (dd, 1H); 7.35 (d, 1H); 4.52 (s, 2H)).

Workup

  1. temperatureThe RM was cooled down to rt
  2. customacetic acid was removed
  3. additionA 2 N NaOH solution was then added until pH=11
  4. customThe organic layer was then separated
  5. washwashed with water (2×)
  6. extractionThe aqueous layer was further extracted with DCM (3×)
  7. customThe combined organic layer was then dried
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe residue crystallized in EtOAc
  11. customThe resulting solid was purified by flash chromatography (Flashmaster
  12. customThe solid crystallized again in EtOAc/Et2O
  13. filtrationIt was filtered
  14. customdried under vacuum

Sources & evidence

ORD record
ord-f007b8190885442a9a70824099f87cb1
Source dataset
uspto-grants-2014_09
Patent number
US08822468B2

Reaction notes

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