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

HRID 1432608Notes

Reaction equation

HRID 1432608 reaction equation
C1COCC1.Br[C:7]1[N:11]([CH3:12])[N:10]=[CH:9][N:8]=1.Br[C:14]1[C:15]([CH3:35])=[C:16]([C:19]2[N:23]3[N:24]=[C:25]([CH3:33])[CH:26]=[C:27]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[C:22]3=[N:21][C:20]=2[CH3:34])[S:17][CH:18]=1>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]>[CH2:29]([CH:28]([C:27]1[C:22]2[N:23]([C:19]([C:16]3[S:17][CH:18]=[C:14]([C:7]4[N:11]([CH3:12])[N:10]=[CH:9][N:8]=4)[C:15]=3[CH3:35])=[C:20]([CH3:34])[N:21]=2)[N:24]=[C:25]([CH3:33])[CH:26]=1)[CH2:31][CH3:32])[CH3:30]

Participants

7

Reactant 3

HCID 8028Tetrahydrofuran2×HCID 1401211H-1,2,4-Triazole, 5-bromo-1-methyl-HCID 579329703-(4-Bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Product 1

HCID 579330058-(1-ethyl-propyl)-2,6-dimethyl-3-[3-methyl-4-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazineYield 19%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
65 °C

Procedure

To a slurry of 0.05 g/mL of Reike® Zn in THF (3.0 mL, 2.29 mmol) is added a solution of 5-bromo-1-methyl-1H-[1,2,4]triazole and THF (2 mL). The solution was heated at 65° C. for 1 hour, cooled to ambient temperature and the excess Zn allowed to settle for 1 hour. The solution was transferred to a flask containing 3-(4-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (example Rupp-152) (0.32 g, 0.70 mmol) and PdCl2(dppf) (0.028 g, 0.038 mmol). The solution is heated at 65° C. overnight, diluted with EtOAc (30 mL), washed with sat. NH4Cl (30 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO (50%-100% Et2O) to furnish the title compound (0.058 g, 0.15 mmol, 19%). 1H NMR (CDCl3) δ 0.86 (t, J=7.5 Hz, 6H), 1.73-1.92 (m, 4H), 2.11 (s, 3H), 2.47 (s, 3H), 2.49 (s, 3H), 3.27-3.37 (m, 1H), 3.97 (s, 3H), 6.68 (s, 1H), 7.64 (s, 1H), 7.99 (s, 1H). LC/MS (m/z): calcd. for C21H26N6S (M+H)+: 395.2; found: 395.4.

Workup

  1. temperaturecooled to ambient temperature
  2. customThe solution was transferred to a flask
  3. temperatureThe solution is heated at 65° C. overnight
  4. washwashed with sat. NH4Cl (30 mL)
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue is purified by ISCO (50%-100% Et2O)

Sources & evidence

ORD record
ord-4d0b1c5010ba43e79761c2ae597001b8
Source dataset
uspto-grants-2009_11
Patent number
US07612067B2

Reaction notes

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