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

HRID 57512

반응식

HRID 57512 반응식
[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

참가 물질

7

반응물 4

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

생성물 1

HCID 904228011-(4-chloro-2-fluorophenyl)-1H-imidazole-4-carbaldehyde수율 69.7%

시약·촉매·용매 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)촉매HCID 6228Dimethylformamide용매

반응 조건

온도
110 °C

실험 절차

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.

후처리

  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

출처 및 근거

ORD 기록
ord-7ab25a18753c4a488517c853fd2dd259
출처 데이터셋
uspto-grants-2016_09
특허 번호
US09434719B2

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