1H-1,2,4-Triazole, 5-bromo-1-methyl- → 3-[3-chloro-4-(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 1432725Notes

Reaction equation

HRID 1432725 reaction equation
Br[C:2]1[C:3]([Cl:23])=[C:4]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])[S:5][CH:6]=1.Br[C:25]1[N:29]([CH3:30])[N:28]=[CH:27][N:26]=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]>[Cl:23][C:3]1[C:2]([C:25]2[N:29]([CH3:30])[N:28]=[CH:27][N:26]=2)=[CH:6][S:5][C:4]=1[C:7]1[N:11]2[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]2=[N:9][C:8]=1[CH3:22]

Participants

6

Reactant 2

HCID 1401211H-1,2,4-Triazole, 5-bromo-1-methyl-HCID 579330783-(4-Bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Product 1

HCID 579330213-[3-chloro-4-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazineYield 9%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
65 °C

Procedure

To a flask of 3-(4-bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.20 g, 0.49 mmol) is added 0.5 g/mL Reike® Zn (1.3 mL, 0.97 mmol). The slurry is heated at 65° C. for 1 hour, placed in a centrifuge for 5 minutes, and the solution transferred to a flask containing 5-bromo-1-methyl-1H-[1,2,4]triazole (0.12 g, 0.73 mmol) and PdCl2(dppf) (0.018 g, 0.024 mmol). The solution is heated at 65° C. overnight, diluted with EtOAc (20 mL), washed with sat. NH4Cl (15 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO flash chromatography (20%-50% EtOAc gradient) furnish the title compound (0.018 g, 0.043 mmol, 9%). 1H NMR (CDCl3) δ 0.87 (t, J=7.5 Hz, 6H), 1.74-1.92 (m, 4H), 2.51 (s, 3H), 2.52 (s, 3H), 3.26-3.37 (m, 1H), 3.95 (s, 3H), 6.72 (s, 1H), 7.82 (s, 1H), 8.01 (s, 1H). LC/MS (m/z): calcd. for C20H23ClN6S (M+H)+: 415.2; found: 415.3.

Workup

  1. customthe solution transferred to a flask
  2. temperatureThe solution is heated at 65° C. overnight
  3. washwashed with sat. NH4Cl (15 mL)
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue is purified by ISCO flash chromatography (20%-50% EtOAc gradient)

Sources & evidence

ORD record
ord-e965cf772eb04c0f9725c8a4414f1041
Source dataset
uspto-grants-2009_11
Patent number
US07612067B2

Reaction notes

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