反应详情

温度

70 °C

6-Acetoxy-7-methoxyquinazolin-4-one (International Patent Application WO 96/15118, Example 39 thereof; 21.4 kg, 89.3 mol) was suspended in toluene (150 kg). To this was added N-ethyldiisopropylamine (13.3 kg, 103 mol). The brown suspension was heated to 70° C. then phosphorus oxychloride (36.0 kg, 228 mol) was charged. The reaction mixture was stirred at 70° C. for 5 hours. Further toluene (84.0 kg) was added followed by 3-chloro-2-fluoroaniline (14.88 kg, 102 mol). The reaction mixture was stirred at 70° C. for 2 hours during which time a solid precipitated. The suspension was cooled to 25° C. and held at this temperature for 93 hours. The reaction mixture was filtered and the filter cake washed with toluene (2×55.5 kg). The cake was further washed with a mixture of ethanol (24.5 kg) and water (32.0 kg) twice, then ethanol (50.5 kg) twice and the solid then dried under vacuum to give the title product as a beige solid (33.4 kg, 78%); 1H NMR: 2.37 (s, 3H), 4.00 (s, 3H), 7.34 (ddd, 1H), 7.48 (s, 1H), 7.52 (ddd, 1H), 7.61 (ddd, 1H), 8.62 (s, 1H), 8.86 (s, 1H); Mass Spectrum: 362.4, 364.4.

1. stirringThe reaction mixture was stirred at 70° C. for 2 hours during which time a solid
2. customprecipitated
3. temperatureThe suspension was cooled to 25° C.
4. waitheld at this temperature for 93 hours
5. filtrationThe reaction mixture was filtered
6. washthe filter cake washed with toluene (2×55.5 kg)
7. washThe cake was further washed with a mixture of ethanol (24.5 kg) and water (32.0 kg) twice
8. dry with materialethanol (50.5 kg) twice and the solid then dried under vacuum