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

HRID 1432650Notes

Reaction equation

HRID 1432650 reaction equation
[CH3:1][N:2]1[CH:6]=[N:5][CH:4]=[N:3]1.C1COCC1.[Li]CCCC.Br[C:18]1[S:22][C:21]([C:23]2[N:27]3[N:28]=[C:29]([CH3:37])[CH:30]=[C:31]([CH:32]([CH2:35][CH3:36])[CH2:33][CH3:34])[C:26]3=[N:25][C:24]=2[CH3:38])=[C:20]([CH3:39])[C:19]=1[CH3:40]>CCOC(C)=O.[Cl-].[Cl-].[Zn+2].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]>[CH3:39][C:20]1[C:19]([CH3:40])=[C:18]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][N:5]=2)[S:22][C:21]=1[C:23]1[N:27]2[N:28]=[C:29]([CH3:37])[CH:30]=[C:31]([CH:32]([CH2:33][CH3:34])[CH2:35][CH3:36])[C:26]2=[N:25][C:24]=1[CH3:38]

Participants

8

Reactant 4

HCID 8028Tetrahydrofuran2×HCID 224591H-1,2,4-Triazole, 1-methyl-HCID 579330573-(5-Bromo-3,4-dimethyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazineHCID 178418339Butyllithium

Product 1

HCID 579330993-[3,4-dimethyl-5-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazineYield 70%

Reagents, catalysts & solvents 3

HCID 3007855ZincchlorideCatalystHCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 8857Ethyl AcetateSolvent

Procedure

To a −78° C. solution of 1-methyl-1,2,4-triazole (0.056 mL, 0.74 mmol) and THF (2 mL) is added a 1.6 M solution of n-BuLi in hexanes (0.46 mL, 0.74 mmol). The solution is warmed to ambient temperature and stirred for 30 minutes. The solution is cooled to 0° C., a 0.5 M solution of ZnCl2 in THF (4.70 mL, 2.33 mmol) is added and the solution warmed to ambient temperature and stirred for 30 minute. 3-(5-bromo-3,4-dimethyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.10 g, 0.25 mmol) and PdCl2(dppf) (0.009 g, 0.012 mmol) is added and the solution 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 column chromatography (15%-60% EtOAc/hexane gradient), followed by a second purification by ISCO column chromatography (100% Et2O) furnish the title compound (0.07 g, 0.17 mmol, 70%). 1H NMR (CDCl3) δ 0.87 (t, J=7.5 Hz, 6H), 1.73-1.92 (m, 4H), 2.06 (s, 3H), 2.29 (s, 3H), 2.47 (s, 3H), 2.51 (s, 3H), 3.27-3.37 (m, 1H), 3.97 (s, 3H), 6.69 (s, 1H), 8.00 (s, 1H). LC/MS (m/z): calcd. for C22H28N6S (M+H)+: 409.6; found: 409.2.

Workup

  1. temperatureThe solution is cooled to 0° C.
  2. temperaturethe solution warmed to ambient temperature
  3. stirringstirred for 30 minute
  4. temperaturethe solution heated at 65° C. overnight
  5. washwashed with sat. NH4Cl (20 mL)
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe residue is purified by ISCO column chromatography (15%-60% EtOAc/hexane gradient)
  10. customfollowed by a second purification by ISCO column chromatography (100% Et2O)

Sources & evidence

ORD record
ord-7ccf50c609774b468f32c1794d0af5ff
Source dataset
uspto-grants-2009_11
Patent number
US07612067B2

Reaction notes

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