Tetrahydrofuran → HCID 57932916, compound

HRID 1432658Notes

Reaction equation

HRID 1432658 reaction equation
C1COCC1.Br[C:7]1[N:11]([CH3:12])[N:10]=[CH:9][N:8]=1.[CH2:13]([CH:15]([C:18]1[C:19]2[N:20]([C:25]([C:29]3[S:30][C:31](I)=[CH:32][C:33]=3[O:34][CH3:35])=[C:26]([CH3:28])[N:27]=2)[N:21]=[C:22]([CH3:24])[CH:23]=1)[CH2:16][CH3:17])[CH3:14]>CCOC(C)=O.[Zn].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>[CH2:13]([CH:15]([C:18]1[C:19]2[N:20]([C:25]([C:29]3[S:30][C:31]([C:7]4[N:11]([CH3:12])[N:10]=[CH:9][N:8]=4)=[CH:32][C:33]=3[O:34][CH3:35])=[C:26]([CH3:28])[N:27]=2)[N:21]=[C:22]([CH3:24])[CH:23]=1)[CH2:16][CH3:17])[CH3:14]

Participants

7

Reactant 3

HCID 8028Tetrahydrofuran2×HCID 1401211H-1,2,4-Triazole, 5-bromo-1-methyl-HCID 68839933HCID 68839933, compound

Product 1

HCID 57932916HCID 57932916, compoundYield 62%

Reagents, catalysts & solvents 3

HCID 23994ZincCatalyst2×HCID 178418397HCID 178418397, compoundCatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
65 °C

Procedure

To a slurry of 0.05 g/mL of Reike® Zn in THF (2.8 mL, 2.11 mmol) is added 5-bromo-1-methyl-1H-[1,2,4]triazole and THF (2 mL). The solution is heated at 65° C. for 1 hour, cooled to ambient temperature and the excess Zn allowed to settle for 1 hour. The solution is transferred to a flask containing 8-(1-ethyl-propyl)-3-(5-iodo-3-methoxy-thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.32 g, 0.70 mmol) and Pd(PPh3)4 (0.041 g, 0.035 mmol). The solution is heated at 65° C. overnight, diluted with EtOAc (30 mL) washed with sat. NH4Cl (30 mL). The aqueous phase is extracted with EtOAc (20 mL). The combined organic layers are dried over MgSO4, filtered and concentrated. The reside is purified by ISCO column chromatography (20%-65% EtOAc/hexane gradient) followed by ISCO column chromatography (100% Et2O) furnish the title compound (0.19 g, 0.46 mmol, 62%). 1H NMR (CDCl3) δ 0.86 (t, J=7.5 Hz, 6H), 1.73-1.91 (m, 4H), 2.51 (s, 3H), 2.52 (s, 3H), 3.26-3.37 (m, 1H), 3.92 (s, 3H), 4.15 (s, 3H), 6.67 (s, 1H), 7.48 (s, 1H), 7.89 (s, 1H). LC/MS (m/z): calcd. for C21H26N6OS (M+H)+: 411.5. found: 411.3.

Workup

  1. temperaturecooled to ambient temperature
  2. customThe solution is transferred to a flask
  3. temperatureThe solution is heated at 65° C. overnight
  4. washwashed with sat. NH4Cl (30 mL)
  5. extractionThe aqueous phase is extracted with EtOAc (20 mL)
  6. dry with materialThe combined organic layers are dried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe reside is purified by ISCO column chromatography (20%-65% EtOAc/hexane gradient)

Sources & evidence

ORD record
ord-804e14497b294914ab7b68e4149dd0d4
Source dataset
uspto-grants-2009_11
Patent number
US07612067B2

Reaction notes

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