Hydrochloric Acid → 8-(1-Ethyl-propyl)-2,6-dimethyl-3-(3-methyl-benzofuran-2-yl)-imidazo[1,2-b]pyridazine

HRID 226099Notes

Reaction equation

HRID 226099 reaction equation
[CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[Li]CCCC.[CH2:16]([CH:18]([C:21]1[C:22]2[N:23]([C:28](I)=[C:29]([CH3:31])[N:30]=2)[N:24]=[C:25]([CH3:27])[CH:26]=1)[CH2:19][CH3:20])[CH3:17].Cl>[Cl-].[Cl-].[Zn+2].C1COCC1>[CH2:16]([CH:18]([C:21]1[C:22]2[N:23]([C:28]([C:3]3[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[C:2]=3[CH3:1])=[C:29]([CH3:31])[N:30]=2)[N:24]=[C:25]([CH3:27])[CH:26]=1)[CH2:19][CH3:20])[CH3:17]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 889393-MethylbenzofuranHCID 577526818-(1-Ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazineHCID 178418339Butyllithium

Product 1

HCID 577526598-(1-Ethyl-propyl)-2,6-dimethyl-3-(3-methyl-benzofuran-2-yl)-imidazo[1,2-b]pyridazineYield 60%

Reagents, catalysts & solvents 2

HCID 3007855ZincchlorideCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A THF solution (6 mL) of 3-methyl-benzofuran (200 mg, 1.51 mmol) is cooled to −78° C. under N2 then treated with nBuLi (1.6 M in hexane, 1.0 mL, 1.6 mmol). After 5 min at −78° C., the solution is warmed to 0° C. for 10 minutes, then to room temperature for 10 min. The mixture is then cooled to −78° C. and treated with ZnCl2 (Aldrich, 0.5 M in THF, 3.2 mL, 1.6 mmol). The resulting mixture is warmed to room temperature and treated with 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (235.3 mg, 0.69 mmol) and PdCl2(dppf)-CH2Cl2 complex (Aldrich, 64 mg, 0.078 mmol). The mixture is heated to 60° C. for 4 hours, then poured into 1 N HCl (60 mL) and extracted with ethyl acetate (2×60 mL). The organic extract is washed with aq. brine, dried over Na2SO4, filtered, and concentrated. The crude product is purified by chromatography using hexane-ethyl acetate gradient (100% hexane to 20% ethyl acetate in hexane) to elute the product. Obtained is 8-(1-ethyl-propyl)-2,6-dimethyl-3-(3-methyl-benzofuran-2-yl)-imidazo[1,2-b]pyridazine as a solid (143.8 mg, 60% yield). ES-MS (m/z): calc'd for C22H25N3O: 347.20. found 348.5 (M+H)+1H NMR (400 mHz, CDCl3): δ 7.65 (d, J=8.4 Hz, 1H), 7.57 (d, J=7.9 Hz, 1H), 7.41-7.31 (m, 2H), 6.76 (br s, 1H), 3.38 (br s, 1H), 2.56 (s, 6H), 2.32 (s, 3H), 1.94-1.81 (m, 4H), 0.91 (t, J=7.5 Hz, 6H) ppm.

Workup

  1. waitto room temperature for 10 min
  2. temperatureThe mixture is then cooled to −78° C.
  3. temperatureThe resulting mixture is warmed to room temperature
  4. temperatureThe mixture is heated to 60° C. for 4 hours
  5. extractionextracted with ethyl acetate (2×60 mL)
  6. extractionThe organic extract
  7. washis washed with aq. brine
  8. dry with materialdried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe crude product is purified by chromatography
  12. washto elute the product
  13. customObtained

Sources & evidence

ORD record
ord-93b31b462982465d97b9bba50ca0f87e
Source dataset
uspto-grants-2009_07
Patent number
US07557103B2

Reaction notes

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