Cesium carbonate → 1-(4-chloro-2-fluorophenyl)-1H-imidazole-4-carbaldehyde

HRID 57512

Reaktionsgleichung

Reaktionsgleichung von HRID 57512
[NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12](I)=[C:11]([F:16])[CH:10]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN[C@@H]1CCCC[C@H]1NC>CN(C=O)C.[Cu]I>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:1]2[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]2)=[C:11]([F:16])[CH:10]=1

Komponenten

7

Edukt 4

HCID 10796Cesium carbonateHCID 764281H-Imidazole-4-carbaldehydeHCID 2733821trans-N,N'-dimethyl-1,2-cyclohexanediamineHCID 27365624-Chloro-2-fluoro-1-iodobenzene

Produkt 1

HCID 904228011-(4-chloro-2-fluorophenyl)-1H-imidazole-4-carbaldehydeAusbeute 69,7 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)KatalysatorHCID 6228DimethylformamideLösungsmittel

Reaktionsbedingungen

Temperatur
110 °C

Versuchsvorschrift

To 1H-imidazole-4-carbaldehyde (2.56 g, 26.6 mmol), 4-chloro-2-fluoro-1-iodobenzene (0.739 g, 2.88 mmol) and Cs2CO3 (1.564 g, 4.80 mmol) in DMF (50 mL) was added copper(I) iodide (0.023 g, 0.120 mmol) and (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (0.068 g, 0.480 mmol). The reaction was heated to 110° C. for 18 hours. The reaction mixture was then cooled to room temperature and filtered, and washed with EtOAc (100 mL). The organic was washed with water (2×30 mL) and brine (30 mL), dried (Na2SO4) and concentrated. The residue was purified by silica gel chromotography to give 1-(4-chloro-2-fluorophenyl)-1H-imidazole-4-carbaldehyde (451 mg), to which was added (S)-2-methylpropane-2-sulfinamide (0.29 g, 2.4 mmol), CuSO4 (0.638 g, 4 mmol) and DCE (10 mL). The reaction was heated to 65° C. for 18 hours. The reaction was cooled to rt, filtered and concentrated to give (S,E)-N-((1-(4-chloro-2-fluorophenyl)-1H-imidazol-4-yl)methylene)-2-methylpropane-2-sulfinamide, to which was added DCM (20 mL). The reaction mixture was cooled to −70° C. and methylmagnesium bromide (1.33 ml, 4 mmol) was added dropwise to the solution. The reaction was stirred for two hours and the cold bath was then removed, and the reaction was allowed to warm to rt and stir for 30 minutes. The reaction was cooled to 0° C. and HCl (1M) was added cautiously to quench until aqueous pH=8. The phases were separated and the aqueous layer was extracted with DCM (2×30 mL). Combined organic was dried (Na2SO4) and concentrated to give (S)—N—((S)-1-(1-(4-chloro-2-fluorophenyl)-1H-imidazol-4-yl)ethyl)-2-methylpropane-2-sulfinamide (130 mg), which was then dissolved in MeOH (5 mL) and HCl (0.5 mL, 4M) was added. The reaction was stirred for one hour and concentrated to give product (100 mg). LCMS m/z 240.1 (M+H)+; Rt-0.50 min.

Aufarbeitung

  1. temperatureThe reaction mixture was then cooled to room temperature
  2. filtrationfiltered
  3. washwashed with EtOAc (100 mL)
  4. washThe organic was washed with water (2×30 mL) and brine (30 mL)
  5. dry with materialdried (Na2SO4)
  6. concentrationconcentrated
  7. customThe residue was purified by silica gel chromotography

Quellen und Nachweise

ORD-Eintrag
ord-7ab25a18753c4a488517c853fd2dd259
Quelldatensatz
uspto-grants-2016_09
Patentnummer
US09434719B2

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