Tetrahydrofuran → 8-(1-Ethyl-propyl)-3-(3-methoxy-5-pyridin-3-yl-thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

HRID 1432656Notes

Reaction equation

HRID 1432656 reaction equation
I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C1COCC1.[Li]C(C)(C)C.Br[C:19]1[S:23][C:22]([C:24]2[N:28]3[N:29]=[C:30]([CH3:38])[CH:31]=[C:32]([CH:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[C:27]3=[N:26][C:25]=2[CH3:39])=[C:21]([O:40][CH3:41])[CH:20]=1>CCOC(C)=O.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:34]([CH:33]([C:32]1[C:27]2[N:28]([C:24]([C:22]3[S:23][C:19]([C:2]4[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=4)=[CH:20][C:21]=3[O:40][CH3:41])=[C:25]([CH3:39])[N:26]=2)[N:29]=[C:30]([CH3:38])[CH:31]=1)[CH2:36][CH3:37])[CH3:35]

Participants

8

Reactant 4

HCID 8028TetrahydrofuranHCID 707143-IodopyridineHCID 579329853-(5-Bromo-3-methoxy-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazineHCID 178418306HCID 178418306, compound

Product 1

HCID 579330258-(1-Ethyl-propyl)-3-(3-methoxy-5-pyridin-3-yl-thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazineYield 61%

Reagents, catalysts & solvents 3

HCID 3007855ZincchlorideCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8857Ethyl AcetateSolvent

Procedure

To a −78° C. solution of 3-iodo-pyridine (0.32 g, 1.56 mmol) and 0.5 M ZnCl2 in THF (3.20 mL, 1.59 mmol) is added t-BuLi (2.27 mL, 3.85 mmol). The solution is warmed to ambient temperature and stirred for 30 minutes. 3-(5-bromo-3-methoxy-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.26 g, 0.64 mmol) and Pd(PPh3)4 (0.037 g, 0.032 mmol) are added and the solution heated at 50° C. for 1 hour, cooled to ambient temperature and stirred overnight. The solution is diluted with EtOAc (30 mL), washed with sat. NH4Cl (2×30 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (20%-50% EtOAc/hexane gradient), furnish the title compound (0.16 g, 0.39 mmol, 61%). 1H NMR (CDCl3) δ 0.87 (t, J=7.5 Hz, 6H), 1.74-1.91 (m, 4H), 2.52 (s, 3H), 2.55 (s, 3H), 3.28-3.38 (m, 1H), 3.93, (3H), 6.67 (s, 1H), 7.26 (d, J=3.5 Hz, 1H), 7.31-7.36 (m, 1H), 7.88-7.92 (m, 1H), 8.55 (d, J=4.5 Hz, 1H), 8.92 (d, J=1.8 Hz, 1H). LC/MS (m/z): calcd. for C23H26N4OS (M+H)+: 407.6; found: 407.4.

Workup

  1. temperaturethe solution heated at 50° C. for 1 hour
  2. temperaturecooled to ambient temperature
  3. stirringstirred overnight
  4. washwashed with sat. NH4Cl (2×30 mL)
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue is purified by ISCO column chromatography (20%-50% EtOAc/hexane gradient)

Sources & evidence

ORD record
ord-d275d785bb9f43839fd5763dc26ac7cc
Source dataset
uspto-grants-2009_11
Patent number
US07612067B2

Reaction notes

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