Ammonium Chloride → 8-(1-Ethyl-propyl)-2,6-dimethyl-3-(2-methyl-furan-3-yl)-imidazo[1,2-b]pyridazine

HRID 1432693Notes

Reaction equation

HRID 1432693 reaction equation
Br[C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH3:7].[Li]CCCC.[CH2:13]([CH:15]([C:18]1[C:19]2[N:20]([C:25](I)=[C:26]([CH3:28])[N:27]=2)[N:21]=[C:22]([CH3:24])[CH:23]=1)[CH2:16][CH3:17])[CH3:14].[NH4+].[Cl-]>[Cl-].[Cl-].[Zn+2].C1COCC1>[CH2:13]([CH:15]([C:18]1[C:19]2[N:20]([C:25]([C:2]3[CH:6]=[CH:5][O:4][C:3]=3[CH3:7])=[C:26]([CH3:28])[N:27]=2)[N:21]=[C:22]([CH3:24])[CH:23]=1)[CH2:16][CH3:17])[CH3:14]

Participants

7

Reactant 4

HCID 25517Ammonium ChlorideHCID 6414843-Bromo-2-methylfuranHCID 577526818-(1-Ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazineHCID 178418339Butyllithium

Product 1

HCID 579329758-(1-Ethyl-propyl)-2,6-dimethyl-3-(2-methyl-furan-3-yl)-imidazo[1,2-b]pyridazineYield 70%

Reagents, catalysts & solvents 2

HCID 3007855ZincchlorideCatalystHCID 8028TetrahydrofuranSolvent

Procedure

A THF solution (10 mL) of 3-bromo-2-methyl furan (prepared as described above) (1.06 gm, 6.58 mmol) is cooled to −78° C. under N2 then treated with nBuLi (1.6 M in hexane, 4.1 mL, 6.6 mmol). After 10 minutes at −78° C., the mixture is treated with ZnCl2 (Aldrich, 0.5 M in THF, 13.2 mL, 6.6 mmol). The resulting mixture is warmed to room temperature then treated with 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (1.13 gm, 3.29 mmol) and PdCl2(dppf)-CH2Cl2 complex (Aldrich, 257 mg, 0.31 mmol). The mixture is heated to 60° C. for 4 hours, then poured into sat. NH4Cl (50 mL) and extracted with diethyl ether (2×50 mL). The combined organic extracts are washed with sat. NaCl, 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 title product (685 mg, 70% yield) as an oil. ES-MS (m/z): calc'd for C18H23N3O: 297.2. found 298.2 (M+H); 1H NMR (400 mHz, CDCl3): δ 7.45 (d, J=2.0 Hz, 1H), 6.63 (s, 1H), 6.60 (d, J=2.0 Hz, 1H), 3.35-3.31 (m, 1H), 2.51 (s, 3H), 2.44 (s, 3H), 2.30 (s, 3H), 1.88-1.75 (m, 4H), 0.86 (t, J=7.5 Hz, 6H).

Workup

  1. temperatureThe mixture is heated to 60° C. for 4 hours
  2. extractionextracted with diethyl ether (2×50 mL)
  3. washThe combined organic extracts are washed with sat. NaCl
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude product is purified by chromatography

Sources & evidence

ORD record
ord-36c92b4235de4a46863710602c0eab68
Source dataset
uspto-grants-2009_11
Patent number
US07612067B2

Reaction notes

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