反应详情

温度

65 °C

6-amino-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one (450 kg, 1.00 mol eq) is stirred in a mixture of methanol (1971 kg) and water (1610 kg) under a nitrogen atmosphere with heating to about 65° C. To this is added a solution of 2,4-dichloro-5-fluoro-pyrimidine in dichloromethane (545 kg 2,4-dichloro-5-fluoro-pyrimidine, 1.40 mol eq, about 50% w/w solution) over a period of about 4 hours, during which dichloromethane is distilled off. The mixture is then stirred at about 70° C. until distillation is complete and then at reflux for about 15 hours. This is then cooled to about 45° C. and filtered. The filtered solid is washed twice with methanol (2×675 kg) and then dried under vacuum at about 55° C. Once dry, the solid is slurried in 85% w/w aqueous formic acid (3150 kg) at about 50° C. for about 6 hours and then filtered. This slurry may be repeated. The resulting damp solid is cooled to about 20° C., washed twice with methanol (2×1800 kg) and dried under vacuum at about 80° C. to give the title compound (577 kg, 77%) as a colored solid.

1. distillationduring which dichloromethane is distilled off
2. temperatureat reflux for about 15 hours
3. temperatureThis is then cooled to about 45° C.
4. filtrationfiltered
5. washThe filtered solid is washed twice with methanol (2×675 kg)
6. customdried under vacuum at about 55° C
7. customOnce dry
8. waitthe solid is slurried in 85% w/w aqueous formic acid (3150 kg) at about 50° C. for about 6 hours
9. filtrationfiltered
10. temperatureThe resulting damp solid is cooled to about 20° C.
11. washwashed twice with methanol (2×1800 kg)
12. customdried under vacuum at about 80° C.