反应详情

温度

-78 °C

A solution of diisopropylamine (0.046 mL, 0.47 mmol) in tetrahydrofuran (2.7 mL) was chilled to -78° C. and butyllithium (0.13 mL, 0.32 mmol, 2.5 N in hexanes) was added dropwise. The solution was stirred 10 minutes and then a solution 6-fluoro-2-methyl-3-(2-methyl-pyridin-3-yl)-3H-quinazolin-4-one (0.10 g, 0.37 mmol) in tetrahydrofuran (0.7 mL) was added dropwise. The solution became intense red and was stirred 30 minutes. In a separate vessel a solution of methyl 2-cyanobenzoate (0.50 g, 3.1 mmol) in tetrahydrofuran (10 mL) was prepared and chilled to -78° C. The cold red anion solution was added to the cold methyl 2-cyanobenzoate solution via canula over 30 seconds. The resulting mixture was stirred 30 minutes at -78° C. and then quenched with saturated aqueous bicarbonate and warmed to ambient temperature. The mixture was diluted with water and repeatedly extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (20×100 mm) with elution proceeding as follows: 10% ethyl acetate/hexane (50 mL), nil; 20% ethyl acetate/hexane (50 mL), unweighedrecovered 3-(2-methyl-pyridin-3-yl)-6-fluoro-2-methyl-3H-quinazolin-4-one; 30% ethyl acetate/hexane (50 mL), nil; 40% ethyl acetate/hexane (50 mL), unweighed recovered methyl 2-cyanobenzoate; 50% ethyl acetate/hexane (50 mL), unweighed impurity; 60% ethyl acetate/hexane (50 mL), mixture of impurity and desired product; 70% ethyl acetate/hexane (50 mL), product. The product containing fractions were combined and concentrated. The residue was triturated with 1% ethyl acetate/ether and the yellow solid which formed was collected and dried to yield 0.017 g (10%) of 2-{2-[6-fluoro-3-(2-methyl-pyridin-3-yl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-1-hydroxy-vinyl}-benzonitrile which had: mp 213-215° C.; 1H NMR δ8.70 (d, J=4 Hz, 1 H), 7.85 (dd, J=3, 8 Hz, 1 H), 7.67 (d, J=7 Hz, 1 H), 7.60 (d, J=9 Hz, 1 H), 7.58-7.38 (m, 6 H), 4.94 (s, 1 H), 2.44 (s, 3 H). Analysis calculated for C23H15FN4O2.0.25 H2O: C, 68.57; H, 3.88; N, 13.91. Found: C, 68.52, 68,91; H, 4.13, 4.21; N, 13.25, 13.28.

1. stirringwas stirred 30 minutes
2. stirringThe resulting mixture was stirred 30 minutes at -78° C.
3. customquenched with saturated aqueous bicarbonate
4. temperaturewarmed to ambient temperature
5. additionThe mixture was diluted with water
6. extractionrepeatedly extracted with ethyl acetate
7. washThe combined extracts were washed with water and brine
8. dry with materialdried over magnesium sulfate
9. concentrationconcentrated
10. customchromatographed on silica gel (20×100 mm) with elution proceeding
11. custom40% ethyl acetate/hexane (50 mL), unweighed recovered methyl 2-cyanobenzoate
12. addition60% ethyl acetate/hexane (50 mL), mixture of impurity and desired product
13. additionThe product containing fractions
14. concentrationconcentrated
15. customThe residue was triturated with 1% ethyl acetate/ether
16. customthe yellow solid which formed
17. customwas collected
18. customdried