反应详情

To a −18° C. solution of 6-chloro-4-(4-bromophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one (2 g, 4.6 mmol) in anhydrous THF (20 mL) was added triethylamine (2.6 mL, 18 mmol). The reaction was stirred for 5 min and then thionyl chloride (0.0.37 mL, 5 mmol) was added dropwise. After 10 min, 0.5M cyclopropylmagnesium bromide in THF (36 mL, 18 mmol) was added. The reaction mixture was warmed from −18° C. to 0° C. and allowed to stir for 6 hours and then quenched with 25 mL 1N aqueous HCl and extracted with 150 mL ethyl acetate. The organic layer was washed with brine (100 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification by normal phase chromatography (120 g silica gel cartridge, linear gradient 10-70% EtOAc/hexanes) followed by crystallization from hexanes gave 6-chloro-4-cyclopropyl-4-(4-bromophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one as a green solid. 1H NMR (CDCl3, 400 MHz) δ 7.56 (s, NH); 7.46 (br d, 2H, J=8.61 Hz); 7.21 (dd, 1H, J=8.42 and 2.20 Hz); 7.12 (br d, 2H, J=7.14 Hz); 6.85 (br m, 1H); 6.68 (d, 1H, J=8.24 Hz); 4.27 (m, 2H); 1.6 (obs, 1H); 0.77 (m, 2H); 0.19 (m, 1H); 0.09 (m, 1H); MS (Electrospray): m/z 459.0 (M+H, Br=79).

1. waitAfter 10 min
2. temperatureThe reaction mixture was warmed from −18° C. to 0° C.
3. stirringto stir for 6 hours
4. customquenched with 25 mL 1N aqueous HCl
5. extractionextracted with 150 mL ethyl acetate
6. washThe organic layer was washed with brine (100 mL)
7. dry with materialdried over MgSO4
8. filtrationfiltered
9. concentrationconcentrated in vacuo
10. customPurification by normal phase chromatography (120 g silica gel cartridge, linear gradient 10-70% EtOAc/hexanes)
11. customfollowed by crystallization from hexanes