2-氟-3-甲基苯甲醛

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of diisopropylamine (0.60 mL, 4.57 mmol) in tetrahydrofuran (27 mL) was chilled to -78° C. and butyllithium (1.30 mL, 3.25 mmol, 2.5 N in hexanes) was added dropwise. The solution was stirred 10 minutes and then a solution 3-(2-chloro-phenyl)-6-fluoro-2-methyl-3H-quinazolin-4-one (1.04 g, 3.60 mmol) in tetrahydrofuran (7 mL) was added dropwise. The solution became intense red and was stirred 30 minutes. In a separate vessel a solution of 2-fluorobenzaldehyde (0.575 mL, 6.33 mmol) in tetrahydrofuran (20 mL) was prepared and chilled to -78 ° C. The cold red anion solution was added to the cold methyl 2-fluorobenzaldehyde solution via canula over 30 seconds. The resulting mixture was stirred 1 hour at -78° C. and then quenched with saturated aqueous bicarbonate and warmed to ambient temperature. The mixture was concentrated and the residue was diluted with water (50 mL), ethyl acetate (10 mL) and saturated aqueous sodium bisulfite (50 mL). This mixture was stirred 1 h and then repeatedly extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate and concentrated. The residues from the two side by side reactions were combined and flash chromatographed on silica gel (45×150 mm) with elution proceeding as follows: 20% ethyl acetate/hexane (500 mL), nil; 30% ethyl acetate/hexane (500 mL) and 40% ethyl acetate/hexane (500 mL), two diastereomers of 3-(2-chloro-phenyl)-6-fluoro-2-[2-(2-fluoro-phenyl)-2-hydroxy-ethyl]-3H-quinazolin-4-one, both as viscous oils. The faster eluting diastereomer weighed 0.231 g (17%) and had: 1H NMR δ7.92 (dd, J=3, 8.5 Hz, 1 H), 7.77 (dd, J=5, 9 Hz, 1 H), 7.60 (dd, J=1.5, 7.5 Hz, 1 H), 7.57-7.55 (m, 1 H), 7.53 (dd, J=3,8 Hz, 1 H), 7.48-7.42 (sym m, 2 H), 7.36-7.31 (m, 1 H), 7.24-7.18 (m,1 H), 7.12 (t, J=7.5 Hz, 1 H), 6.96-6.90 (m, 1 H), 5.65 (br s, 1 H), 5.55 (dd, J=2.5, 9 Hz, 1 H), 2.70 (dd, J=2.5, 17 Hz, 1 H), 2.61 (dd, J=9, 17 Hz, 1 H). The slower eluting diastereomer weighed 0.283 g (21%) and had: 1H NMR δ7.91 (dd, J=3, 9 Hz, 1 H), 7.76 (dd, J=5, 9 Hz, 1 H), 7.58 (dd, J=1.5, 8 Hz, 1 H), 7.54 (dd, J=3, 9 Hz, 1 H), 7.51 (dd, J=1.5, 8 Hz, 1 H), 7.44 (dt, J=2, 8 Hz, 1 H), 7.39 (dt, J=1.5, 8 Hz, 1 H), 7.23-7.17 (m, 1 H), 7.13-7.07 (m, 2 H), 6.98-6.91 (m, 1 H), 5.61 (br s, 1 H), 5.57 (dd, J=4, 8 Hz, 1 H), 2.72-2.60 (m, 2 H). was stirred 30 minutes The resulting mixture was stirred 1 hour at -78° C. quenched with saturated aqueous bicarbonate warmed to ambient temperature The mixture was concentrated the residue was diluted with water (50 mL), ethyl acetate (10 mL) and saturated aqueous sodium bisulfite (50 mL) This mixture was stirred 1 h repeatedly extracted with ethyl acetate The combined extracts were washed with water and brine dried over magnesium sulfate concentrated flash chromatographed on silica gel (45×150 mm) with elution proceeding The faster eluting diastereomer The slower eluting diastereomer

反应条件: temp:22.01; pressure:0.00; stir:

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of diisopropylamine (0.60 mL, 4.57 mmol) in tetrahydrofuran (27 mL) was chilled to -78° C. and butyllithium (1.30 mL, 3.25 mmol, 2.5 N in hexanes) was added dropwise. The solution was stirred 10 minutes and then a solution 3-(2-chloro-phenyl)-6-fluoro-2-methyl-3H-quinazolin-4-one (1.04 g, 3.60 mmol) in tetrahydrofuran (7 mL) was added dropwise. The solution became intense red and was stirred 30 minutes. In a separate vessel a solution of 2-fluorobenzaldehyde (0.575 mL, 6.33 mmol) in tetrahydrofuran (20 mL) was prepared and chilled to -78 ° C. The cold red anion solution was added to the cold methyl 2-fluorobenzaldehyde solution via canula over 30 seconds. The resulting mixture was stirred 1 hour at -78° C. and then quenched with saturated aqueous bicarbonate and warmed to ambient temperature. The mixture was concentrated and the residue was diluted with water (50 mL), ethyl acetate (10 mL) and saturated aqueous sodium bisulfite (50 mL). This mixture was stirred 1 h and then repeatedly extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate and concentrated. The residues from the two side by side reactions were combined and flash chromatographed on silica gel (45×150 mm) with elution proceeding as follows: 20% ethyl acetate/hexane (500 mL), nil; 30% ethyl acetate/hexane (500 mL) and 40% ethyl acetate/hexane (500 mL), two diastereomers of 3-(2-chloro-phenyl)-6-fluoro-2-[2-(2-fluoro-phenyl)-2-hydroxy-ethyl]-3H-quinazolin-4-one, both as viscous oils. The faster eluting diastereomer weighed 0.231 g (17%) and had: 1H NMR δ7.92 (dd, J=3, 8.5 Hz, 1 H), 7.77 (dd, J=5, 9 Hz, 1 H), 7.60 (dd, J=1.5, 7.5 Hz, 1 H), 7.57-7.55 (m, 1 H), 7.53 (dd, J=3,8 Hz, 1 H), 7.48-7.42 (sym m, 2 H), 7.36-7.31 (m, 1 H), 7.24-7.18 (m,1 H), 7.12 (t, J=7.5 Hz, 1 H), 6.96-6.90 (m, 1 H), 5.65 (br s, 1 H), 5.55 (dd, J=2.5, 9 Hz, 1 H), 2.70 (dd, J=2.5, 17 Hz, 1 H), 2.61 (dd, J=9, 17 Hz, 1 H). The slower eluting diastereomer weighed 0.283 g (21%) and had: 1H NMR δ7.91 (dd, J=3, 9 Hz, 1 H), 7.76 (dd, J=5, 9 Hz, 1 H), 7.58 (dd, J=1.5, 8 Hz, 1 H), 7.54 (dd, J=3, 9 Hz, 1 H), 7.51 (dd, J=1.5, 8 Hz, 1 H), 7.44 (dt, J=2, 8 Hz, 1 H), 7.39 (dt, J=1.5, 8 Hz, 1 H), 7.23-7.17 (m, 1 H), 7.13-7.07 (m, 2 H), 6.98-6.91 (m, 1 H), 5.61 (br s, 1 H), 5.57 (dd, J=4, 8 Hz, 1 H), 2.72-2.60 (m, 2 H). was stirred 30 minutes The resulting mixture was stirred 1 hour at -78° C. quenched with saturated aqueous bicarbonate warmed to ambient temperature The mixture was concentrated the residue was diluted with water (50 mL), ethyl acetate (10 mL) and saturated aqueous sodium bisulfite (50 mL) This mixture was stirred 1 h repeatedly extracted with ethyl acetate The combined extracts were washed with water and brine dried over magnesium sulfate concentrated flash chromatographed on silica gel (45×150 mm) with elution proceeding The faster eluting diastereomer The slower eluting diastereomer