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

HRID 1432643Notes

Reaction equation

HRID 1432643 reaction equation
Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8].C1COCC1.[CH2:14]([CH:16]([C:19]1[C:20]2[N:21]([C:26](I)=[C:27]([CH3:29])[N:28]=2)[N:22]=[C:23]([CH3:25])[CH:24]=1)[CH2:17][CH3:18])[CH3:15]>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]>[CH2:14]([CH:16]([C:19]1[C:20]2[N:21]([C:26]([C:2]3[S:3][CH:4]=[CH:5][C:6]=3[C:7]#[N:8])=[C:27]([CH3:29])[N:28]=2)[N:22]=[C:23]([CH3:25])[CH:24]=1)[CH2:17][CH3:18])[CH3:15]

Participants

7

Reactant 3

HCID 8028TetrahydrofuranHCID 120790262-Bromothiophene-3-carbonitrileHCID 577526818-(1-Ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine

Product 1

HCID 579330472-[8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-thiophene-3-carbonitrileYield 42.5%

Reagents, catalysts & solvents 3

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

Procedure

To a solution 0.05 g/mL of Reike® Zn (31 mL, 23.93 mmol) is added 2-bromo-thiophene-3-carbonitrile (Fournari, P. et al. Bull. Soc. Chim. Fr., 1967, 4115) (2.25 g, 11.96 mmol) and THF (5 mL). The solution is heated at a reflux for 2 hours, cooled to ambient temperature and the excess Zn allowed to settle. The solution is transferred via a cannula into a flask of 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (2.5 g, 7.98 mmol) and PdCl2(dppf) (0.29 g, 0.040 mmol). The mixture is heated at 65° C. overnight, diluted with EtOAc (75 mL), washed with sat. NH4Cl (2×75 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (10%-20% EtOAc/hexane gradient) furnish the title compound (1.10 g, 3.39 mmol, 42%). 1H NMR (CDCl3) δ 0.86 (t, J=7.5 Hz, 6H), 1.74-1.91 (m, 4H), 2.55 (s, 3H), 2.61 (s, 3H), 3.25-3.34 (m, 1H), 6.75 (s, 1H), 7.35 (d, J=5.2 Hz, 1H), 7.53 (d, J=5.2 Hz, 1H). LC/MS (m/z): calcd. for C18H20N4S (M+H)+: 325.5; found: 325.2.

Workup

  1. temperatureThe solution is heated at
  2. temperaturea reflux for 2 hours
  3. temperatureThe mixture is heated at 65° C. overnight
  4. washwashed with sat. NH4Cl (2×75 mL)
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue is purified by ISCO column chromatography (10%-20% EtOAc/hexane gradient)

Sources & evidence

ORD record
ord-77b7e8fc145e45c7bd48a21e00004a67
Source dataset
uspto-grants-2009_11
Patent number
US07612067B2

Reaction notes

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