Tetrahydrofuran → 3-[3-chloro-5-(2-methyl-2H-pyrazol-3-yl)-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

HRID 1432639Notes

Reaction equation

HRID 1432639 reaction equation
[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.C1COCC1.[Li]CCCC.Br[C:18]1[S:22][C:21]([C:23]2[N:27]3[N:28]=[C:29]([CH3:37])[CH:30]=[C:31]([CH:32]([CH2:35][CH3:36])[CH2:33][CH3:34])[C:26]3=[N:25][C:24]=2[CH3:38])=[C:20]([Cl:39])[CH:19]=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]>[Cl:39][C:20]1[CH:19]=[C:18]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[S:22][C:21]=1[C:23]1[N:27]2[N:28]=[C:29]([CH3:37])[CH:30]=[C:31]([CH:32]([CH2:33][CH3:34])[CH2:35][CH3:36])[C:26]2=[N:25][C:24]=1[CH3:38]

Participants

8

Reactant 4

HCID 8028TetrahydrofuranHCID 702551H-Pyrazole, 1-methyl-HCID 579329223-(5-Bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazineHCID 178418339Butyllithium

Product 1

HCID 579330023-[3-chloro-5-(2-methyl-2H-pyrazol-3-yl)-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazineYield 50%

Reagents, catalysts & solvents 3

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

Procedure

To a −78° C. solution of 1-methyl-1H-pyrazole (0.12 g, 1.45 mmol) and THF (4 mL) is added 1.6 M n-BuLi (0.91 mL, 1.45 mmol). After 45 minutes 0.5 M ZnCl2 (2.9 mL, 1.45 mmol) is added and the solution is warmed to ambient temperature. After 30 minutes 3-(5-bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (example Rupp-88) (0.30 g, 0.73 mmol) and PdCl2(dppf) (0.027 g, 0.036 mmol) are added and the solution heated at 65° C. overnight, diluted with EtOAc (30 mL), washed with sat. NH4Cl (2×30 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (15%-30% EtOAc/hexane gradient) furnish the title compound (0.15 g, 0.36 mmol, 50%). 1H NMR (CDCl3) δ 0.88 (d, J=7.5 Hz, 6H), 1.74-1.91 (m, 4H), 2.52 (s, 6H), 3.26-3.36 (m, 1H), 4.05 (s, 3H), 6.45 (d, J=1.9 Hz, 1H), 6.71 (s, 1H), 7.14 (s, 1H), 7.49 (d, J=1.9 Hz, 1H). LC/MS (m/z): calcd. for C21H24ClN5S (M+H)+: 414.2; found: 414.2.

Workup

  1. temperaturethe solution heated at 65° C. overnight
  2. washwashed with sat. NH4Cl (2×30 mL)
  3. dry with materialdried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe residue is purified by ISCO column chromatography (15%-30% EtOAc/hexane gradient)

Sources & evidence

ORD record
ord-5f51bf3e35c24cb2ab62211994190c42
Source dataset
uspto-grants-2009_11
Patent number
US07612067B2

Reaction notes

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