Tetrahydrofuran → HCID 57932976, compound

HRID 1432579Notes

Reaction equation

HRID 1432579 reaction equation
Br[C:2]1[S:6][C:5]([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])=[C:4]([CH3:23])[CH:3]=1.C1COCC1.C([Li])CCC.Br[C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1>C(Cl)Cl.[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]>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:5]3[S:6][C:2]([C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)=[CH:3][C:4]=3[CH3:23])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]

Participants

8

Reactant 4

HCID 8028Tetrahydrofuran2×HCID 122863-BromopyridineHCID 579329433-(5-Bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazineHCID 178418339Butyllithium

Product 1

HCID 57932976HCID 57932976, compoundYield 52.8%

Reagents, catalysts & solvents 3

HCID 3007855ZincchlorideCatalystHCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 6344DichloromethaneSolvent

Conditions

Temperature
-78 °C

Procedure

To a −78° C. solution of 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.50 g, 1.27 mmol), and THF (5 mL) is added 1.34 M n-Bu-Li (1.0 mL, 1.34 mmol). The solution is stirred for at −78° C. for 30 minutes and 0.5 M ZnCl2 in THF (2.7 mL, 1.34 mmol) is added and the solution warmed to ambient temperature. After 30 minutes 3-bromopyridine (0.15 mL, 1.53 mmol) and PdCl2(dppf) (0.047 g, 0.064 mmol) is added and the solution heated at 65° C. overnight. The solution is diluted with CH2Cl2 (40 mL), washed with 10% citric acid (20 mL), water (20 mL), brine (20 mL) dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (20%-40% EtOAc/hexane gradient) concentrated and re-dissolved in Et2O. The solution is treated with Darco®-60 for 15 minutes, dried over Na2SO4, and filtered thru Celite® furnish the title compound (0.26 g, 0.67 mmol, 52%). 1H NMR (CDCl3), δ 0.88 (t, J=7.5 Hz, 6H), 1.74-1.92 (m, 4H), 2.17 (s, 3H), 2.50 (s, 3H), 2.52 (s, 3H), 3.28-3.38 (m, 1H), 6.68 (s, 1H), 7.26-7.32 (m, 2H), 7.86 (dt, J=7.9, 1.8 Hz, 1H), 850 (d, J=3.2 Hz, 1H), 8.89 (s, 1H). LC/MS (m/z): calcd. for C23H26N4S (M+H)+: 391.6; found: 391.2.

Workup

  1. temperaturethe solution warmed to ambient temperature
  2. temperaturethe solution heated at 65° C. overnight
  3. washwashed with 10% citric acid (20 mL), water (20 mL), brine (20 mL)
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue is purified by ISCO column chromatography (20%-40% EtOAc/hexane gradient)
  8. concentrationconcentrated
  9. dissolutionre-dissolved in Et2O
  10. additionThe solution is treated with Darco®-60 for 15 minutes
  11. dry with materialdried over Na2SO4
  12. filtrationfiltered

Sources & evidence

ORD record
ord-9379dad72f8d49a7b6773042f914831d
Source dataset
uspto-grants-2009_11
Patent number
US07612067B2

Reaction notes

Loading…