反应详情

To a suspension of N-{1-[(4-amino-2-methylphenyl)methyl]-1H-pyrazol-3-yl}-2,6-difluorobenzamide (for a preparation see Intermediate 33)(400 mg, 1.17 mmol) in water (1.7 ml) in an ice-water bath (internal temperature 5° C.) was added concentrated sulphuric acid specific gravity 1.84 (165 μl, 3.10 mmol) and then a solution of sodium nitrite, super free flowing (90 mg, 1.305 mmol, Aldrich) in ice-cold water (0.5 ml) dropwise. The resulting yellow solution was stirred in an ice-water bath for 30 min. To the mixture was added a solution of potassium iodide, extra pure briquettes (291 mg, 1.75 mmol, Acros) in ice cold ˜1 M sulphuric acid (3 ml). The mixture was allowed to warm to ambient temperature and then heated to 80° C. for 1 h. The mixture was allowed to cool to room temperature for 1 h and was then partitioned between ethyl acetate (50 ml) and water (50 ml). The phases were separated and the organic phase washed with water (20 ml), brine (20 ml), dried (MgSO4), filtered and the solvent removed in vacuo to leave a dark red/brown oil (515 mg). The sample was loaded in dichloromethane and purified on silica 50 g using 0-50% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow oil (223 mg); LCMS: (System 4) MH+=454, tRET=3.14 min.

1. custom(internal temperature 5° C.)
2. temperatureheated to 80° C. for 1 h
3. temperatureto cool to room temperature for 1 h
4. customwas then partitioned between ethyl acetate (50 ml) and water (50 ml)
5. customThe phases were separated
6. washthe organic phase washed with water (20 ml), brine (20 ml)
7. dry with materialdried (MgSO4)
8. filtrationfiltered
9. customthe solvent removed in vacuo