Tetrahydrofuran → 3-[5-(3,5-Dimethyl-isoxazol-4-yl)-3-methyl-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

HRID 1432633Notes

Reaction equation

HRID 1432633 reaction equation
I[C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[CH3:7].C1COCC1.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]>[CH3:8][C:3]1[C:2]([C:15]2[S:19][C:18]([C:20]3[N:24]4[N:25]=[C:26]([CH3:34])[CH:27]=[C:28]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[C:23]4=[N:22][C:21]=3[CH3:35])=[C:17]([CH3:36])[CH:16]=2)=[C:6]([CH3:7])[O:5][N:4]=1

Participants

7

Reactant 3

HCID 8028TetrahydrofuranHCID 6138834-Iodo-3,5-dimethyl-1,2-oxazoleHCID 579329433-(5-Bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Product 1

HCID 579329303-[5-(3,5-Dimethyl-isoxazol-4-yl)-3-methyl-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazineYield 71.1%

Reagents, catalysts & solvents 3

HCID 23994ZincCatalyst2×HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
50 °C

Procedure

To a flask of 4-iodo-3,5-dimethyl-isoxazole (0.34 g, 1.53 mmol) is added a solution of Rieke® zinc 5 g/100 mL in THF (3 mL, 2.29 mmol). The slurry is heated at a reflux for 4 hours, the zinc is allowed to settle and the solution transferred to a flask of 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.30 g, 0.76 mmol) and PdCl2(dppf) (0.028 g, 0.038 mmol). The solution is heated at 50° C. overnight, diluted with EtOAc (20 mL), washed with 0.1 M HCl (15 mL), water (15 mL), brine (15 mL) dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (15%-30% EtOAc/hexane gradient) furnish the title compound (0.22 g, 0.54 mmol, 71%). 1H NMR (CDCl3), δ 0.92 (t, J=7.5 Hz, 6H), 1.78-1.96 (m, 4H), 2.21 (s, 3H), 2.47 (s, 3H), 2.53 (s, 3H), 2.56 (s, 3H), 2.61 (s, 3H), 3.33-3.42 (m, 1H), 6.72 (s, 1H), 6.98 (s, 1H). LC/MS (m/z): calcd. for C23H28N4OS (M+H)+: 409.3; found: 409.2.

Workup

  1. temperatureThe slurry is heated at
  2. temperaturea reflux for 4 hours
  3. washwashed with 0.1 M HCl (15 mL), water (15 mL), brine (15 mL)
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue is purified by ISCO column chromatography (15%-30% EtOAc/hexane gradient)

Sources & evidence

ORD record
ord-1ccab16b28df4427abb5115c2a74435e
Source dataset
uspto-grants-2009_11
Patent number
US07612067B2

Reaction notes

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