反应详情

温度

67 °C

A nitrogen-flushed, suitably equipped 5 L 4-neck round bottom flask is charged with 200 g (0.723 mol, 1.0 eq.) of 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine (A1f) and 2303 g, (2600 mL) of tetrahydrofuran. The mixture is stirred, heated to reflux (67° C.) and 200 mL of distillate is collected. The sample is cooled to 25° C. and 52.7 g (0.940 mol, 55.6 mL, 1.3 eq.) of propargyl alcohol (A1e), 570.3 g (1.808 mol, 2.5 eq.) of tetrabutylammonium fluoride trihydrate and 25.4 g (0.036 mol, 0.05 eq.) of bis(triphenylphosphine)palladium (II) dichloride are added. The sample is stirred, heated to reflux (67° C.) and maintained at this temperature for 2 h or until 5-7% of the starting material A1f remains as determined by HPLC analysis. The sample is cooled to 25° C. and concentrated under reduced pressure (100 mbar, 30° C. maximum internal temperature) to a volume of 1150 mL to remove tetrahydrofuran. 541 g, (600 mL) of ethyl acetate is charged. The sample is again concentrated under reduced pressure (100 mbar, 30° C. maximum internal temperature) to a volume of 1150 mL to remove residual tetrahydrofuran. 2706 g (3000 mL) of ethyl acetate and a solution of 63 g of sodium bicarbonate dissolved in 1500 g (1500 mL) of water are added. The sample is stirred at 25° C. for 10 min and the phases are separated. The organic (top) phase is washed once with 1500 g (1500 mL) of water. The sample is stirred for 10 min and the phases are separated. The organic (top) phase is concentrated under reduced pressure (100 mbar, 30° C. maximum internal temperature) to a volume of 625 mL to remove ethyl acetate. 1582 g (2000 mL) of acetone is added to the concentrate. The sample is stirred, heated to reflux (58° C.) and maintained at this temperature for 30 min. It is then cooled to 40° C. and clarified by filtering through a pad of filter cel. The flask and filter cake are washed twice with 158 g (200 mL, 2×100 mL per wash) of acetone. The sample is concentrated under reduced pressure (100 mbar, 30° C. maximum internal temperature) to a volume of 460 mL. It is then cooled to 4° C. and is hold at this temperature for 1 h. The solids are filtered and the filter cake is washed twice with 158 g (2×100 mL) of cold (4° C.) acetone. The solids are dried at 50° C. for 16 h, to afford 85.6 g (47.4%, corrected) of Compound A1d as a tan, crystalline solid, mp=162-163° C.

1. customA nitrogen-flushed
2. temperatureheated
3. customis collected
4. temperatureThe sample is cooled to 25° C.
5. stirringThe sample is stirred
6. temperatureheated
7. temperatureto reflux (67° C.)
8. temperatureThe sample is cooled to 25° C.
9. concentrationconcentrated under reduced pressure (100 mbar, 30° C. maximum internal temperature) to a volume of 1150 mL
10. customto remove tetrahydrofuran
11. addition541 g, (600 mL) of ethyl acetate is charged
12. concentrationThe sample is again concentrated under reduced pressure (100 mbar, 30° C. maximum internal temperature) to a volume of 1150 mL
13. customto remove residual tetrahydrofuran
14. dissolution2706 g (3000 mL) of ethyl acetate and a solution of 63 g of sodium bicarbonate dissolved in 1500 g (1500 mL) of water
15. additionare added
16. stirringThe sample is stirred at 25° C. for 10 min
17. customthe phases are separated
18. washThe organic (top) phase is washed once with 1500 g (1500 mL) of water
19. stirringThe sample is stirred for 10 min
20. customthe phases are separated
21. concentrationThe organic (top) phase is concentrated under reduced pressure (100 mbar, 30° C. maximum internal temperature) to a volume of 625 mL
22. customto remove ethyl acetate
23. addition1582 g (2000 mL) of acetone is added to the concentrate
24. stirringThe sample is stirred
25. temperatureheated
26. temperatureto reflux (58° C.)
27. temperaturemaintained at this temperature for 30 min
28. temperatureIt is then cooled to 40° C.
29. filtrationby filtering through a pad of filter cel
30. filtrationThe flask and filter cake
31. washare washed twice with 158 g (200 mL, 2×100 mL per wash) of acetone
32. concentrationThe sample is concentrated under reduced pressure (100 mbar, 30° C. maximum internal temperature) to a volume of 460 mL
33. temperatureIt is then cooled to 4° C.
34. customfor 1 h
35. filtrationThe solids are filtered
36. washthe filter cake is washed twice with 158 g (2×100 mL) of cold (4° C.) acetone
37. customThe solids are dried at 50° C. for 16 h
38. customto afford 85.6 g (47.4%, corrected) of Compound A1d as a tan, crystalline solid, mp=162-163° C.