反应详情

温度

70 °C

The reactor was charged at 20° C. with 111.7 g 4,4′-(6-chloropyrimidine-2,4-diyl)dimorpholine 3, 108.5 g K2CO3 and 4.54 g Tetrakis(Triphenylphosphin)Palladium (0). 125 ml water and 500 ml 1,2-Dimethoxyethan were added. The white suspension was warmed within 30 min to 90° C. A solution of 100 g 6-acetamido-4-(trifluoromethyl)pyridin-3-ylboronic acid B3 in 450 ml 1,2-Dimethoxyethan was constantly added within a period of 4½ h. The funnel was washed with 50 ml 1,2-Dimethoxyethan. The reaction mixture was cooled to 70° C. within 30 min. 1000 ml water were added. 1000 ml solvent was removed by distillation (70° C., 400 mbar to 260 mbar). 1000 ml water was added. 1000 ml solvent was removed by distillation (70° C., 400 mbar to 260 mbar). The reaction mixture was cooled to 20° C. within 30 min. The precipitate was collected by filtration and washed with 300 ml water. The reactor was charged with the precipitate and 1900 g 1N HCl were added. The reaction mixture was warmed to 75° C. within 30 min. The reaction mixture was stirred for 3 h at 75° C. The reaction mixture cooled to 20° C. within 1 h and stirred over night at 20° C. The precipitate was removed by filtration and washed with 200 ml water. The reactor was charged with the filtrate and everything was rinsed with 100 ml water. pH was adjusted to pH11.9. 1800 ml Isopropylacetate were added and the mixture was stirred. The phases were separated and the organic layer was collected. Solvent was removed (70° C., 280 mbar) until the volume was reduced to 725 ml. 1800 ml Isopropylacetate were added and the mixture was stirred. The phases were separated and the organic layer was collected. Solvent was removed (70° C., 280 mbar) until the volume was reduced to 725 ml. The reaction mixture was cooled to 20° C. within 30 min and stored over the week end. The reaction mixture was filtered over a bed of HYO and washed with 225 ml Isopropylacetate. The reactor was charged with the filtrate and 735.5 g of solution 1 (61.2 g N-Acetyl-cystein and 600 g water, pH adjusted to pH 7 with 4 N NaOH) were added. The reaction mixture was warmed to 64° C. within 15 min. The reaction mixture was stirred at 64° C. for 2 h. The reaction mixture was cooled to 20° C. within 45 min. The phases were separated and the aqueous layer was removed. 1926.5 ml 1N HCl were added and the mixture was stirred for 15 min. The phases were separated and the aqueous layer was collected. 947 ml 1N HCl were added and the mixture was stirred for 15 min. The phases were separated and the aqueous layer was collected. The organic layer was removed from the reactor. The reactor was charged with the combined aqueous layers. pH was adjusted to pH 2.3. 39 g Silabond were added. The reaction mixture was warmed to 64° C. within 20 min. The reaction mixture was stirred for 2 h at 64° C. The reaction mixture was coiled to 20° C. within 30 min. The precipitate was removed by filtration. The residue was washed with 500 g water. The reactor was charged with the combined filtrates. pH was adjusted to pH 5.0 with 4 N NaOH The reaction mixture was cooled to 0° C. The reaction mixture was stirred for 60 min. The product was collected by filtration and washed with 500 g cold (˜10° C.) water. The product was dried until constant weight was obtained to yield 136.8 g (84.9%) 5-(2,6-Di-4-morpholinyl-4-pyrimidinyl)-4-trifluoromethylpyridin-2-amine 5.

1. temperatureThe white suspension was warmed within 30 min to 90° C
2. washThe funnel was washed with 50 ml 1,2-Dimethoxyethan
3. addition1000 ml water were added
4. custom1000 ml solvent was removed by distillation (70° C., 400 mbar to 260 mbar)
5. addition1000 ml water was added
6. custom1000 ml solvent was removed by distillation (70° C., 400 mbar to 260 mbar)
7. temperatureThe reaction mixture was cooled to 20° C. within 30 min
8. filtrationThe precipitate was collected by filtration
9. washwashed with 300 ml water
10. additionThe reactor was charged with the precipitate and 1900 g 1N HCl
11. additionwere added
12. temperatureThe reaction mixture was warmed to 75° C. within 30 min
13. temperatureThe reaction mixture cooled to 20° C. within 1 h
14. stirringstirred over night at 20° C
15. customThe precipitate was removed by filtration
16. washwashed with 200 ml water
17. additionThe reactor was charged with the filtrate and everything
18. washwas rinsed with 100 ml water
19. addition1800 ml Isopropylacetate were added
20. stirringthe mixture was stirred
21. customThe phases were separated
22. customthe organic layer was collected
23. customSolvent was removed (70° C., 280 mbar) until the volume
24. addition1800 ml Isopropylacetate were added
25. stirringthe mixture was stirred
26. customThe phases were separated
27. customthe organic layer was collected
28. customSolvent was removed (70° C., 280 mbar) until the volume
29. temperatureThe reaction mixture was cooled to 20° C. within 30 min
30. filtrationThe reaction mixture was filtered over a bed of HYO
31. washwashed with 225 ml Isopropylacetate
32. additionThe reactor was charged with the filtrate and 735.5 g of solution 1 (61.2 g N-Acetyl-cystein and 600 g water
33. additionwere added
34. temperatureThe reaction mixture was warmed to 64° C. within 15 min
35. stirringThe reaction mixture was stirred at 64° C. for 2 h
36. temperatureThe reaction mixture was cooled to 20° C. within 45 min
37. customThe phases were separated
38. customthe aqueous layer was removed
39. addition1926.5 ml 1N HCl were added
40. stirringthe mixture was stirred for 15 min
41. customThe phases were separated
42. customthe aqueous layer was collected
43. addition947 ml 1N HCl were added
44. stirringthe mixture was stirred for 15 min
45. customThe phases were separated
46. customthe aqueous layer was collected
47. customThe organic layer was removed from the reactor
48. additionThe reactor was charged with the combined aqueous layers
49. addition39 g Silabond were added
50. temperatureThe reaction mixture was warmed to 64° C. within 20 min
51. stirringThe reaction mixture was stirred for 2 h at 64° C
52. waitThe reaction mixture was coiled to 20° C. within 30 min
53. customThe precipitate was removed by filtration
54. washThe residue was washed with 500 g water
55. additionThe reactor was charged with the combined filtrates
56. temperaturewas cooled to 0° C
57. stirringThe reaction mixture was stirred for 60 min
58. filtrationThe product was collected by filtration
59. washwashed with 500 g cold (˜10° C.) water
60. customThe product was dried until constant weight
61. customwas obtained