Tetrahydrofuran → (2-{5-[8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiophen-2-yl}-pyrrol-1-yl)-dimethyl-amine

HRID 1432578Notes

Reaction equation

HRID 1432578 reaction equation
[CH3:1][N:2]([CH3:8])[N:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.C1COCC1.[Li]CCCC.Br[C:20]1[S:24][C:23]([C:25]2[N:29]3[N:30]=[C:31]([CH3:39])[CH:32]=[C:33]([CH:34]([CH2:37][CH3:38])[CH2:35][CH3:36])[C:28]3=[N:27][C:26]=2[CH3:40])=[C:22]([CH3:41])[CH:21]=1>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]>[CH2:35]([CH:34]([C:33]1[C:28]2[N:29]([C:25]([C:23]3[S:24][C:20]([C:4]4[N:3]([N:2]([CH3:8])[CH3:1])[CH:7]=[CH:6][CH:5]=4)=[CH:21][C:22]=3[CH3:41])=[C:26]([CH3:40])[N:27]=2)[N:30]=[C:31]([CH3:39])[CH:32]=1)[CH2:37][CH3:38])[CH3:36]

Participants

8

Reactant 4

HCID 8028TetrahydrofuranHCID 5735271-(Dimethylamino)pyrroleHCID 579329433-(5-Bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazineHCID 178418339Butyllithium

Product 1

HCID 57933059(2-{5-[8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiophen-2-yl}-pyrrol-1-yl)-dimethyl-amineYield 95.1%

Reagents, catalysts & solvents 3

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

Procedure

To a 0° C. solution 1-(dimethylamino)-pyrrole (0.24 mL, 2.04 mmol) and THF (4 mL) is added 1.24 M n-BuLi (1.73 mL, 2.14 mmol). The solution is warmed to ambient temperature and stirred for two hours. 0.5 M ZnCl2 (4.28 mL, 2.14 mmol) is added and the solution is stirred for one hour. 3-(5-Bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.40 g, 1.02 mmol) and PdCl2(dppf) (0.037 g, 0.051 mmol) is added and the solution is heated at 65° C. overnight. The solution is diluted with EtOAc (30 mL), washed with sat. NH4Cl (30 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO flash chromatography (15%-20% EtOAc gradient) furnish the title compound (0.41 g, 0.97 mmol, 95%). 1H NMR (CDCl3) δ 0.87 (t, J=7.5 Hz, 6H), 1.73-1.91 (m, 4H), 2.11 (s, 3H), 2.51 (s, 6H), 2.83 (s, 6H), 3.29-3.39 (m, 1H), 6.18-6.21 (m, 1H), 6.35 (dd, J=4.0, 1.8 Hz, 1H), 6.65 (s, 1H), 6.98 (dd, J=4.0, 1.8 Hz, 1H), 7.25 (s, 1H). LC/MS (m/z): calcd. for C24H31N5S (M+H)+: 422.2; found: 422.4.

Workup

  1. stirringthe solution is stirred for one hour
  2. temperaturethe solution is heated at 65° C. overnight
  3. washwashed with sat. NH4Cl (30 mL)
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue is purified by ISCO flash chromatography (15%-20% EtOAc gradient)

Sources & evidence

ORD record
ord-a011127dc43d441486b1ae29f168e74d
Source dataset
uspto-grants-2009_11
Patent number
US07612067B2

Reaction notes

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