反应详情

4-Amino-3′-fluoro[1,1′-biphenyl]-3-carbonitrile was prepared from 3-fluorophenyl boronic acid and 2-amino-5-bromobenzonitrile according to procedure A. A solution of 4-amino-3′-fluoro[1,1′-biphenyl]-3-carbonitrile (6.65 g, 31.3 mmol) in anhydrous THF (100 mL) was treated drop wise at rt under nitrogen with methylmagnesium bromide (3.0 M in ether, 21 mL, 63 mmol). After addition, the reaction mixture was heated at gentle reflux for 1.5 hours, cooled to rt, and treated with 3N aqueous hydrogen chloride solution (30 mL). The mixture was heated at reflux for 3 hours, cooled to ambient temperature, and adjusted to pH 5-6 by addition of a saturated aqueous sodium carbonate solution. Ethyl acetate (100 mL) was added, organic layer was separated and aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried (MgSO4) and evaporated. The residue was purified by a silica gel column chromatography (hexane:ethyl acetate/3:1) to afford 1-(4-amino-3′-fluoro[1,1 ′-biphenyl]-3-yl)ethanone (3.1 g, 43%): mp 156-157° C.

1. additionAfter addition
2. temperaturethe reaction mixture was heated
3. temperatureat gentle reflux for 1.5 hours
4. temperatureThe mixture was heated
5. temperatureat reflux for 3 hours
6. temperaturecooled to ambient temperature
7. customorganic layer was separated
8. extractionaqueous layer was extracted with ethyl acetate (3×50 mL)
9. dry with materialThe combined organic layers were dried (MgSO4)
10. customevaporated
11. customThe residue was purified by a silica gel column chromatography (hexane:ethyl acetate/3:1)