Tetrahydrofuran → 2-[8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-5-pyridin-3-yl-thiophene-3-carbonitrile

HRID 1432647Notes

Reaction equation

HRID 1432647 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]([C:40]#[N: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[C:40]#[N: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 8028Tetrahydrofuran2×HCID 707143-IodopyridineHCID 57932902HCID 57932902, compoundHCID 178418306HCID 178418306, compound

Product 1

HCID 579329072-[8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-5-pyridin-3-yl-thiophene-3-carbonitrileYield 71.2%

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), 0.5 M ZnCl2 in THF (3.20 mL, 1.59 mmol), and THF (2 mL) is added 1.7 M t-BuLi (1.85 mL, 3.15 mmol). The solution is warmed to ambient temperature and stirred for 30 minutes. 5-Bromo-2-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-thiophene-3-carbonitrile (0.21 g, 0.52 mmol) and Pd(PPh3)4 (0.03 g, 0.026 mmol) are added and the solution heated at 55° C. for 1 hour, cooled to ambient temperature and stirred overnight, diluted with EtOAc (50 mL), washed with sat. NH4Cl (2×40 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (15%-40% EtOAc/hexane gradient), furnish the title compound (0.15 g, 0.37 mmol, 71%). 1H NMR (CDCl3) δ 0.87 (t, J=7.5 Hz, 6H), 1.74-1.92 (m, 4H), 2.58 (s, 3H), 2.66 (s, 3H), 3.26-3.35 (m, 1H), 6.78 (s, 1H), 7.34-7.46 (m, 1H), 7.56 (s 1H), 7.91 (d, J=7.1 Hz, 1H), 8.62 (s, 1H), 8.91 (s, 1H). LC/MS (m/z): calcd. for C23H23N5S (M+H)+: 402.6; found: 402.4.

Workup

  1. temperaturethe solution heated at 55° C. for 1 hour
  2. temperaturecooled to ambient temperature
  3. stirringstirred overnight
  4. washwashed with sat. NH4Cl (2×40 mL)
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue is purified by ISCO column chromatography (15%-40% EtOAc/hexane gradient)

Sources & evidence

ORD record
ord-60c663f14d924ac7bec1ee1eee204a82
Source dataset
uspto-grants-2009_11
Patent number
US07612067B2

Reaction notes

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