反应详情

温度

20 °C

Within 20 min. 61 ml (633 mmol) of POCl3 were added dropwise to 34 ml (200 mmol) of diisopropyl ethylamine at 5° C. to 10° C. followed by stirring at 5° C. to 10° C. for 15 min. Then 23.5 g (66 mmol) of 4-[4,6-dihydroxy-5-(2-methoxy-phenoxy)-pyrimidine-2-yl]-pyridine-2-carboxylic acid amide were added in four portions under cooling followed by stirring at 90° C. for 25 hr. The reaction mixture was cooled down to 20° C. and transferred to a new flask together with 50 ml of dichloromethane. Volatile components (i.e. excess of POCl3) was removed by evaporation from 20° C. to 70° C. followed by re-distillation with 100 ml of toluene. After adding 250 ml of dichloromethane to the residue (88 g of a black oil) the solution was heated to 35° C. to 40° C. and 80 ml of de-ionized water were added dropwise within 30 min. whereby the pH was kept constant by the subsequent addition of 28% NaOH solution (60 ml) within 5 to 6 hr. The mixture was stirred at 35° C. to 40° C. for 30 min. followed by removal of dichloromethane by distillation. The resulting suspension was allowed to cool down to 20° C. and was stirred for additional 2 hr. The solid was filtered off under suction, washed with 500 ml of water and dried at 70° C., 2000 Pa for 16 hr. There were obtained 21.3 g (86% of theory) of 4-[4,6-dichloro-5-(2-methoxy-phenoxy)-pyrimidine-2-yl]-pyridine-2-carbonitrile with a HPLC purity of 94.3% (w/w).

1. temperatureunder cooling
2. stirringby stirring at 90° C. for 25 hr
3. customVolatile components (i.e. excess of POCl3) was removed by evaporation from 20° C. to 70° C.
4. distillationfollowed by re-distillation with 100 ml of toluene
5. additionAfter adding 250 ml of dichloromethane to the residue (88 g of a black oil) the solution
6. temperaturewas heated to 35° C. to 40° C.
7. addition80 ml of de-ionized water were added dropwise within 30 min. whereby the pH
8. additionwas kept constant by the subsequent addition of 28% NaOH solution (60 ml) within 5 to 6 hr
9. stirringThe mixture was stirred at 35° C. to 40° C. for 30 min.
10. customfollowed by removal of dichloromethane by distillation
11. temperatureto cool down to 20° C.
12. stirringwas stirred for additional 2 hr
13. filtrationThe solid was filtered off under suction
14. washwashed with 500 ml of water
15. customdried at 70° C.
16. wait2000 Pa for 16 hr