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

HRID 1432648Notes

Reaction equation

HRID 1432648 reaction equation
Br[C:2]1[C:3]([CH3:23])=[C:4]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])[S:5][CH:6]=1.[Br-].[CH3:25][C:26]1[N:31]=[C:30]([Zn+])[CH:29]=[CH:28][CH:27]=1.C1COCC1>CCOC(C)=O.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]>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:4]3[S:5][CH:6]=[C:2]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([CH3:25])[N:31]=4)[C:3]=3[CH3:23])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]

Participants

6

Reactant 3

HCID 8028TetrahydrofuranHCID 579329703-(4-Bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazineHCID 178426002HCID 178426002, compound

Product 1

HCID 579329058-(1-Ethyl-propyl)-2,6-dimethyl-3-[3-methyl-4-(6-methyl-pyridin-2-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazineYield 31%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
65 °C

Procedure

To a flask containing 3-(4-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (below) (0.25 g, 0.64 mmol) and PdCl2(dppf) (0.023 g, 0.032 mmol) is added a solution of 0.5 M 6-methyl-2-pyridylzinc bromide in THF (2.5 mL, 1.27 mmol). The solution is heated at 65° C. overnight, diluted with EtOAc (25 mL), washed with sat. NH4Cl (20 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO (15%-20% EtOAc gradient) and is chromatographed (50×250 C18 Symmetry column, 10-70% water: 0.1% TFA/ACN: 0.1% TFA gradient). The residue is dissolved in Et2O (20 mL), washed with sat. NaHCO3 (15 mL) dried over MgSO4, filtered and concentrated to furnish the title compound (0.066 g, 1.57 mmol, 31%). 1H NMR (CDCl3) δ 0.87 (t, J=7.5 Hz, 6H), 1.73-1.91 (m, 4H), 2.20 (s, 3H), 2.47 (s, 3H), 2.49 (s, 3H), 2.61 (s, 3H), 3.29-3.38 (m, 1H), 6.66 (s, 1H), 7.09 (d, J=7.5 Hz, 1H), 7.43 (d, J=7.8 Hz, 1H), 7.54 (dd, J=7.5, 7.8 Hz, 1H), 7.72 (s, 1H). LC/MS (m/z): calcd. for C24H28N4S (M+H)+: 405.2; found: 405.3.

Workup

  1. washwashed with sat. NH4Cl (20 mL)
  2. dry with materialdried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe residue is purified by ISCO (15%-20% EtOAc gradient)
  6. customis chromatographed (50×250 C18 Symmetry column, 10-70% water: 0.1% TFA/ACN: 0.1% TFA gradient)
  7. dissolutionThe residue is dissolved in Et2O (20 mL)
  8. washwashed with sat. NaHCO3 (15 mL)
  9. dry with materialdried over MgSO4
  10. filtrationfiltered
  11. concentrationconcentrated

Sources & evidence

ORD record
ord-c5a0aedb812d48329e42998cc8ea8b1d
Source dataset
uspto-grants-2009_11
Patent number
US07612067B2

Reaction notes

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