Tetrahydrofuran → 8-(1-Ethyl-propyl)-3-[5-(4-fluoro-phenyl)-3-methyl-thiophen-2-yl]-2,6-dimethyl-imidazo[1,2-b]pyridazine

HRID 1432586Notes

Reaction equation

HRID 1432586 reaction equation
C1COCC1.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.Br[C:15]1[S:19][C:18]([C:20]2[N:24]3[N:25]=[C:26]([CH3:34])[CH:27]=[C:28]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[C:23]3=[N:22][C:21]=2[CH3:35])=[C:17]([CH3:36])[CH:16]=1>CCOC(C)=O.[Zn].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:30]([CH:29]([C:28]1[C:23]2[N:24]([C:20]([C:18]3[S:19][C:15]([C:7]4[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=4)=[CH:16][C:17]=3[CH3:36])=[C:21]([CH3:35])[N:22]=2)[N:25]=[C:26]([CH3:34])[CH:27]=1)[CH2:32][CH3:33])[CH3:31]

Participants

7

Reactant 3

HCID 8028TetrahydrofuranHCID 99931-Bromo-4-fluorobenzeneHCID 579329433-(5-Bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Product 1

HCID 579331028-(1-Ethyl-propyl)-3-[5-(4-fluoro-phenyl)-3-methyl-thiophen-2-yl]-2,6-dimethyl-imidazo[1,2-b]pyridazineYield 25%

Reagents, catalysts & solvents 3

HCID 23994ZincCatalystHCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 8857Ethyl AcetateSolvent

Procedure

A slurry of 0.05 g/mL of Reike® Zn in THF (0.26 g, 4.01 mmol) and 1-bromo-4-fluoro-benzene (0.29 mL, 2.68 mmol) is heated at a reflux overnight. The solution is filtered under nitrogen. 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.35 g, 0.89 mmol) and PdCl2(dppf) (0.033 g, 0.045 mmol) are added, and the solution is heated at a reflux overnight diluted with EtOAc (30 mL), washed with 10% citric acid (20 mL), water (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (10%-15% EtOAc/hexane gradient) furnish the title compound (0.091 g, 0.22 mmol, 25%). 1H NMR (CDCl3), δ 0.88 (t, J=7.5 Hz, 6H), 1.74-1.92 (m, 4H), 2.15 (s, 3H), 2.50 (s, 3H), 2.52 (s, 3H), 3.30-3.38 (m, 1H), 6.68 (s, 1H), 7.08 (d, J=8.8 Hz, 2H), 7.18 (s, 1H), 7.59 (dd, J=8.5, 5.3 Hz, 2H). LC/MS (m/z): calcd. for C24H26FN3S (M+H)+: 408.7; found: 408.3.

Workup

  1. filtrationThe solution is filtered under nitrogen
  2. temperaturethe solution is heated at a reflux overnight
  3. washwashed with 10% citric acid (20 mL), water (20 mL), brine (20 mL)
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue is purified by ISCO column chromatography (10%-15% EtOAc/hexane gradient)

Sources & evidence

ORD record
ord-fc3feafe80b14902899b1ca55bcc05c5
Source dataset
uspto-grants-2009_11
Patent number
US07612067B2

Reaction notes

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