反应详情

温度

15 °C

To a 5-L three-necked flask with a thermometer controller, a mechanical stirrer, and a condenser protected under N2 was charged EtOH (570 g), THF (1330 g), boronic acid 7 (100 g, 255.6 mmol, 1.0 eq.), 2-amino-4,6-dichloropyrimidine 126 g (768.3 mmol, 3.0 eq.), PPh3 (0.87 g, 3.32 mmol, 1.3 mol %) and Pd(OAc)2 (0.373 g, 1.66 mmol, 0.65 mol %). The flask was then degassed by three vacuum/nitrogen fill cycles and stirred at about 10-20° C. for about 10-20 minutes. To the stirring solution was added an aqueous solution of KHCO3 (92 g, 918.9 mmol, 3.6 eq in 579 g of water) over about 30-50 minutes to control the evolution of CO2 gas). The flask was then degassed again by three vacuum/nitrogen fill cycles. The resulting solution was then refluxed at about 68˜72° C. for 21˜23 hours and the reaction was determined to be complete base on HPLC analysis. The reaction mixture was concentrated to ˜750 mL under reduced pressure at 35˜40° C. and then flushed with water (300 mL×2). The concentrated solution was diluted with water (600 g) and stirred for 15˜30 minutes at 20˜25° C. After filtration, the filter cake was washed with water (200 g×2). The filtrate was extracted with EtOAc (500 g×2). The combined EtOAc layer was washed with water (300 g). THF (1000 g) and toluene (730 g) were then added to the combined aqueous layer and the mixture was acidified to pH 2.5˜3.5 with 6 N HCl (−100 g) at 20˜25° C. The layers were separated and NaCl (500 g) was added to the aqueous layer then extracted with EtOAc (400 g). The combined organic layer was treated with active carbon (50 g) at 65˜68° C. for 8˜10 hours twice. The resulting mixture was concentrated under vacuum to ˜300 mL at 30˜40° C. and then flushed with toluene (500 g). The resulting mixture was cooled to 0˜5° C. and stirred for 60˜80 minutes at 0˜5° C., and then filtered. The wet cake was washed with toluene (43 g) and dried in vacuum oven at 40˜45° C. for 12 hours to afford 82.3 g of the monochloride toluene solvate 8 as an off-white solid in 66% yield corrected for 80 w % purity (96.3 A %).

1. customTo a 5-L three-necked flask with a thermometer controller, a mechanical stirrer, and a condenser protected under N2
2. customThe flask was then degassed by three vacuum/nitrogen
3. customThe flask was then degassed again by three vacuum/nitrogen
4. temperatureThe resulting solution was then refluxed at about 68˜72° C. for 21˜23 hours
5. concentrationThe reaction mixture was concentrated to ˜750 mL under reduced pressure at 35˜40° C.
6. customflushed with water (300 mL×2)
7. additionThe concentrated solution was diluted with water (600 g)
8. stirringstirred for 15˜30 minutes at 20˜25° C
9. filtrationAfter filtration
10. washthe filter cake was washed with water (200 g×2)
11. extractionThe filtrate was extracted with EtOAc (500 g×2)
12. washThe combined EtOAc layer was washed with water (300 g)
13. additionTHF (1000 g) and toluene (730 g) were then added to the combined aqueous layer
14. customwas acidified to pH 2.5˜3.5 with 6 N HCl (−100 g) at 20˜25° C
15. customThe layers were separated
16. additionNaCl (500 g) was added to the aqueous layer
17. extractionthen extracted with EtOAc (400 g)
18. additionThe combined organic layer was treated with active carbon (50 g) at 65˜68° C. for 8˜10 hours twice
19. concentrationThe resulting mixture was concentrated under vacuum to ˜300 mL at 30˜40° C.
20. customflushed with toluene (500 g)
21. temperatureThe resulting mixture was cooled to 0˜5° C.
22. stirringstirred for 60˜80 minutes at 0˜5° C.
23. filtrationfiltered
24. washThe wet cake was washed with toluene (43 g)
25. customdried in vacuum oven at 40˜45° C. for 12 hours