反应详情

温度

-78 °C

Two identical reactions were run side by side. A solution of diisopropylamine (0.120 mL, 0.91 mmol) in tetrahydrofuran (5.4 mL) was chilled to -78° C. and butyllithium (0.26 mL, 0.65 mmol, 2.5 N in hexanes) was added dropwise. The solution was stirred 10 minutes and then a solution 3-(2-chloro-pyridin-3-yl)-6-fluoro-2-methyl-3H-quinazolin-4-one (0.204 g, 0.70 mmol) in tetrahydrofuran (5 mL) was added dropwise. The solution became intense red and was stirred 30 minutes. In a separate vessel a solution of methyl 2-cyanobenzoate (1.02 g, 6.33 mmol) in tetrahydrofuran (15 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 1 hour 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 residues from the two side by side reactions were combined and flash chromatographed on silica gel (40×220 mm) with elution proceeding as follows: 10% ethyl acetate/hexane (250 mL), nil; 20% ethyl acetate/hexane (250 mL), nil; 30% ethyl acetate/hexane (50 mL), unweighed impurity; 40% ethyl acetate/hexane (250 mL), unweighed recovered 3-(2-chloro-pyridin-3-yl)-6-fluoro-2-methyl-3H-quinazolin-4-one; 50% ethyl acetate/hexane (250 mL), nil; 60% ethyl acetate/hexane (250 mL), desired product (tlc Rf =0.3 with 50% ethyl acetate/hexane on silica gel). The product containing fractions were combined and concentrated. The residue was triturated with ether and the light yellow solid which formed was collected and dried to yield 0.093 g (17%) 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 217-218° C.; 1H NMR δ8.60 (dd, J=3, 5 Hz, 1 H), 7.85 (dd, J=3, 8 Hz, 1 H), 7.81 (dd, J=2, 8 Hz, 1 H), 7.67 (d, J=7 Hz, 1 H), 7.58-7.42 (m, 6 H), 4.98 (s, 1 H). Analysis calculated for C21H12ClFN4O2 : C, 63.09; H, 2.89; N, 13.38. Found: C, 62.90; H, 2.81; N, 13.01.

1. stirringwas stirred 30 minutes
2. stirringThe resulting mixture was stirred 1 hour 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. customflash chromatographed on silica gel (40×220 mm) with elution proceeding
11. custom40% ethyl acetate/hexane (250 mL), unweighed recovered 3-(2-chloro-pyridin-3-yl)-6-fluoro-2-methyl-3H-quinazolin-4-one
12. additionThe product containing fractions
13. concentrationconcentrated
14. customThe residue was triturated with ether
15. customthe light yellow solid which formed
16. customwas collected
17. customdried