反应详情

温度

20 °C

A nitrogen-flushed, suitably equipped 5 L 4-neck round bottom flask is charged with 250 g (1.097 mol, 140.4 mL, 1.0 eq.) of 5-bromo-2,4-dichloropyrimidine (A1h) and 1127 g, (1250 mL) of ethyl acetate. The content is stirred at 20° C. and 283.5 g (2.194 mol, 382.0 mL, 2.0 eq.) of N,N-diisopropylethylamine is added. A solution of 102.8 g (1.207 mol, 119 mL, 1.1 eq.) of cyclopentylamine (A1g) dissolved in 1127 g, (1250 mL) of ethyl acetate is added over 60 min. An 18° C. to 36° C. exotherm is observed. The solution is warmed to 40° C. This temperature is maintained for at least 6 h or until all the starting material A1h, is consumed as determined by HPLC analysis. The resulting slurry is cooled to 25° C. and 500 g (500 mL) of water is added. The content is stirred for 15 min and the phases are allowed to separate. The bottom (aqueous) layer is removed and the organic layer is washed once more with 500 g (500 mL) of water. The sample is stirred for 15 min, and the phases are allowed to separate. The bottom (aqueous) layer is removed. The organic phase is concentrated (atmospheric pressure) to a volume of 1500 mL (batch temp=82° C.). 684 g (1 L) of heptane is added and the concentration is resumed to a volume of 1500 mL (batch temp=85° C.). Again, 684 g (1 L) of heptane is added and the concentration is resumed to a volume of 1500 mL (batch temp=96° C.). The sample is cooled to 50° C. and seeded. The cooling is continued to 4° C. and the temperature is maintained at 4° C. for 1 h. The solids are filtered and the filter cake is washed once with 137 g (200 mL) of cold (4° C.) heptane. The solids are dried at 50° C. for 16 h, to afford 259.0 g (88.0%, corrected) of Compound A1f as a white, crystalline solid, mp=95-96° C.

1. customA nitrogen-flushed
2. additionis added over 60 min
3. customAn 18° C. to 36° C. exotherm
4. temperatureThe solution is warmed to 40° C
5. temperatureThis temperature is maintained for at least 6 h or until all the starting material A1h
6. customis consumed
7. temperatureThe resulting slurry is cooled to 25° C.
8. addition500 g (500 mL) of water is added
9. stirringThe content is stirred for 15 min
10. customto separate
11. customThe bottom (aqueous) layer is removed
12. washthe organic layer is washed once more with 500 g (500 mL) of water
13. stirringThe sample is stirred for 15 min
14. customto separate
15. customThe bottom (aqueous) layer is removed
16. concentrationThe organic phase is concentrated (atmospheric pressure) to a volume of 1500 mL (batch temp=82° C.)
17. addition684 g (1 L) of heptane is added
18. concentrationthe concentration
19. customis resumed to a volume of 1500 mL (batch temp=85° C.)
20. additionAgain, 684 g (1 L) of heptane is added
21. concentrationthe concentration
22. customis resumed to a volume of 1500 mL (batch temp=96° C.)
23. temperatureThe sample is cooled to 50° C.
24. customis continued to 4° C.
25. temperaturethe temperature is maintained at 4° C. for 1 h
26. filtrationThe solids are filtered
27. washthe filter cake is washed once with 137 g (200 mL) of cold (4° C.) heptane
28. customThe solids are dried at 50° C. for 16 h
29. customto afford 259.0 g (88.0%, corrected) of Compound A1f as a white, crystalline solid, mp=95-96° C.