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Hydrochloric Acid → 8-(1-Ethyl-propyl)-3-(5-fluoro-3-methyl-benzofuran-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

HRID 226096
Notes
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Reaction equation

HRID 226096 reaction equation
[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=1.[Li]CCCC.[CH2:17]([CH:19]([C:22]1[C:23]2[N:24]([C:29](I)=[C:30]([CH3:32])[N:31]=2)[N:25]=[C:26]([CH3:28])[CH:27]=1)[CH2:20][CH3:21])[CH3:18].Cl>[Cl-].[Cl-].[Zn+2].O.C1COCC1>[CH2:17]([CH:19]([C:22]1[C:23]2[N:24]([C:29]([C:8]3[O:9][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:11][C:6]=4[C:7]=3[CH3:10])=[C:30]([CH3:32])[N:31]=2)[N:25]=[C:26]([CH3:28])[CH:27]=1)[CH2:20][CH3:21])[CH3:18]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 116798475-Fluoro-3-methylbenzofuranHCID 577526818-(1-Ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazineHCID 178418339Butyllithium

Product 1

HCID 577526538-(1-Ethyl-propyl)-3-(5-fluoro-3-methyl-benzofuran-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazineYield 54%

Reagents, catalysts & solvents

3
HCID 3007855ZincchlorideCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

A THF solution (6 mL) of 5-fluoro-3-methyl-benzofuran (187.0 mg, 1.25 mmol) is cooled to −78° C. under N2 then treated with nBuLi (1.6 M in hexane, 1.0 mL, 1.6 mmol). After 10 min at −78° C., ZnCl2 (Aldrich, 0.5 M in THF, 3.0 mL, 1.5 mmol) is added. 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 (212.4 mg, 0.62 mmol) and PdCl2(dppf)-CH2Cl2 complex (Aldrich, 60 mg, 0.073 mmol). The mixture is heated to 65° C. for 18 hours, then poured into H2O, acidified with 1 N HCl then extracted with ethyl acetate. The organic extract is ished 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 give the title compound as a solid (121.7 mg, 54% yield).

Workup

  1. temperatureThe mixture is heated to 65° C. for 18 hours
  2. extractionthen extracted with ethyl acetate
  3. extractionThe organic extract
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude product is purified by chromatography

Sources & evidence

ORD record
ord-ba71d9cb7a5f4195b1e5ddf93c141fec
Source dataset
uspto-grants-2009_07
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07557103B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes